CN104447553B - Preparation method for ivabradine and intermediate thereof - Google Patents
Preparation method for ivabradine and intermediate thereof Download PDFInfo
- Publication number
- CN104447553B CN104447553B CN201310432959.8A CN201310432959A CN104447553B CN 104447553 B CN104447553 B CN 104447553B CN 201310432959 A CN201310432959 A CN 201310432959A CN 104447553 B CN104447553 B CN 104447553B
- Authority
- CN
- China
- Prior art keywords
- ivabradine
- transfer catalyst
- phase transfer
- preparation
- dehydrogenation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 135
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract 29
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 97
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 229920000570 polyether Polymers 0.000 claims abstract description 24
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 5
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000706 filtrate Substances 0.000 claims description 24
- 125000001453 quaternary ammonium group Chemical class 0.000 claims description 23
- -1 sulfonyloxy Chemical group 0.000 claims description 22
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 18
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 18
- 208000035126 Facies Diseases 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000002738 chelating agent Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 5
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 150000004696 coordination complex Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- 150000003863 ammonium salts Chemical class 0.000 claims 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 241000723346 Cinnamomum camphora Species 0.000 claims 1
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 claims 1
- UZIQYAYUUNMDMU-UHFFFAOYSA-N N.[Br+] Chemical compound N.[Br+] UZIQYAYUUNMDMU-UHFFFAOYSA-N 0.000 claims 1
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 229960002598 fumaric acid Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 238000004440 column chromatography Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002131 composite material Substances 0.000 abstract description 3
- 239000004721 Polyphenylene oxide Substances 0.000 abstract description 2
- 239000003880 polar aprotic solvent Substances 0.000 abstract 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 description 103
- 230000003197 catalytic effect Effects 0.000 description 18
- 230000004044 response Effects 0.000 description 17
- 239000000463 material Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 239000004519 grease Substances 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910021645 metal ion Inorganic materials 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002191 fatty alcohols Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 206010054949 Metaplasia Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- 238000003408 phase transfer catalysis Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 229940048879 dl tartaric acid Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229960000504 ivabradine hydrochloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- RLXDCJUIXHSXQD-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O.OC(=O)C(O)=O RLXDCJUIXHSXQD-UHFFFAOYSA-N 0.000 description 1
- 229940085675 polyethylene glycol 800 Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012070 reactive reagent Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000007086 side reaction 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
- 238000007614 solvation Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0239—Quaternary ammonium compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/068—Polyalkylene glycols
-
- B01J35/19—
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
Abstract
The invention provides a preparation method for ivabradine and an intermediate thereof dehydrogenated ivabradine. The preparation method of the dehydrogenated ivabradine comprises: step a1, enabling a compound shown as a formula II and a compound shown as a formula III to have a nucleophilic substitution reaction in a polar aprotic solvent in the presence of an acid binding agent and a composite phase-transfer catalyst to generate dehydrogenated ivabradine; and step b1, performing separation and purification on dehydrogenated ivabradine obtained in the step a1. The composite phase-transfer catalyst is composed of a quaternary ammonium salt phase-transfer catalyst and a polyether phase-transfer catalyst with the mass ratio of 1-10:1, and X in the formula II is selected from Cl, Br, I, sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, p-methylbenzene sulfonyloxy, o-methylbenzene sulfonyloxy or m-methylbenzene sulfonyloxy. The method is capable of substantially shortening the time of nucleophilic substitution reaction, improving product purity, avoiding a column chromatography process and reducing production cost.
Description
Technical field
The invention belongs to technical field of medicine synthesis is and in particular to Ivabradine and its intermediate dehydrogenation Ivabradine
Preparation method.
Background technology
Ivabradine and its addition salts with pharmaceutically acceptable acid have very high pharmacology and therapeutic value,
Can be widely used for treating or preventing the various clinical conditions of myocardial ischemia, such as angina pectoriss, myocardial infarction and adjoint rhythm disturbance
Deng, it may also be used for the treatment of heart failure, it is a kind of to treat the boundless cardiovascular drugs of new generation of prospect.
Hydrochloric acid Ivabradine, chemistry is entitled: 7,8- dimethoxy -3- (3- [[(1s) (4,5- dimethoxy benzo ring fourths
Alkane -1- base) methyl]-methylamino] propyl group) -1,3,4,5- tetrahydrochysene -2h- benzazepine -2- keto hydrochlorides, the following institute of its structure
Show:
Preparation method and the therapeutic use of Ivabradine hydrochloride is described in ep0534859.In this patent, using elder generation
Carry out nucleophilic substitution and carry out the method for catalytic hydrogenation again preparing Ivabradine, specific preparation method is as follows:
The method is to prepare the main flow route of Ivabradine at present, but has the disadvantage in that the response time is longer, reaction
Temperature is higher, and the wherein nucleophilic substitution time is more than 15.0h, and reaction temperature is 90-100 DEG C, in addition nucleophilic substitution
Preparation dehydrogenation Ivabradine and catalytic hydrogenation prepare the last handling process that Ivabradine two-step reaction is both needed to column chromatography, organic
Solvent consumption is big, and yield low (about 17.0%), there is a problem of heavy-metal residual, process costs higher it is difficult to realize industry
Metaplasia is produced.
In recent years, with scientific and technical development, the new method that some prepare Ivabradine is suggested, but these methods
Have such problems as that raw material or intermediate are difficult to obtain.
Content of the invention
For the problems referred to above, it is an object of the present invention to provide a kind of intermediate dehydrogenation of Ivabradine she cut down cloth
The preparation method of Lei Ding, the method is compound using be made up of quaternary ammonium salt-type phase transfer catalyst and polyethers phase transfer catalyst
Dehydrogenation Ivabradine prepared by phase transfer catalyst, can significantly shorten the response time, reduces reaction temperature, improves product pure
Spend, and raw material easily obtains.
Another object of the present invention is to providing a kind of preparation method of Ivabradine.
For reaching above-mentioned purpose, the present invention provides a kind of preparation method of the dehydrogenation Ivabradine shown in formula i, comprising:
Step a1: make the compound shown in formula ii and the compound shown in formula iii in acid binding agent and composite phase transfer catalysis
There is the dehydrogenation Ivabradine shown in nucleophilic substitution production i in polar non-solute in the presence of agent；
Step b1: the dehydrogenation Ivabradine obtaining in step a1 is carried out with separation, purification；
Wherein, the quaternary ammonium salt-type phase transfer catalyst that described complex phase transfer catalyst is 1～10:1 by mass ratio and poly-
Ethers phase transfer catalyst form, described x be selected from cl, br, i, sulfonyloxy, methanesulfonyloxy group, phenylsulfonyloxy, to toluene
Sulfonyloxy, adjacent tosyloxy or a tosyloxy.
Preferably, described quaternary ammonium salt-type phase transfer catalyst be selected from benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide,
Benzalkonium bromide or benzyltrimethylammonium bromide, more preferably benzalkonium bromide；Preferably, described polyethers phase transfer catalyst is selected from and gathers
Ethylene glycol, polyoxyethylene fatty alcohol or polyoxyethylene alkylphenol, more preferably Polyethylene Glycol, particularly preferred molecular weight is 200～800
Between Polyethylene Glycol.
Preferably, the consumption of described complex phase transfer catalyst is 2.0%～6.0% of compound quality shown in formula, more
Preferably 4.0%.
Preferably, in described complex phase transfer catalyst, described quaternary ammonium salt-type phase transfer catalyst and described polyethers phase
The mass ratio of transfer catalyst is 3～7:1, more preferably 5:1.
Preferably, described acid binding agent is selected from sodium carbonate, potassium carbonate, potassium bicarbonate or sodium bicarbonate；
Preferably, described polar non-solute be selected from dimethylformamide (dmf), dimethyl acetylamide (dmac), two
Methyl sulfoxide (dmso) or acetonitrile (acn).
Preferably, the nucleophilic substitution in described step a1 is carried out at 80-85 DEG C；
Described step b1 includes: after the compound shown in formula ii is reacted with the compound shown in formula iii, cooling, and filter, receive
Collection filtrate, filtrate is added in saturated nacl aqueous solution, is extracted with ethyl acetate, separates organic faciess, after concentrating under reduced pressure
To dehydrogenation Ivabradine.
The present invention further provides a kind of preparation method of Ivabradine, described Ivabradine is by using above-mentioned side
The dehydrogenation Ivabradine preparation of method preparation.
Preferably, the preparation method of described Ivabradine comprises the following steps:
Step a2: prepare the dehydrogenation Ivabradine shown in formula i using said method；
Step b2: the dehydrogenation Ivabradine shown in dissolution type i, and by salt-forming reaction obtain the dehydrogenation shown in formula iv she
Cut down mine-laying and determine acylate；
Step c2: the dehydrogenation Ivabradine acylate shown in dissolution type iv, obtained shown in formula v by hydrogenation reaction
Ivabradine acylate；
Step d2: the Ivabradine acylate shown in dissolution type v, obtain after adjusting ph value, extraction, separation, washing
Ivabradine.
Preferably, the preparation method of described Ivabradine comprises the following steps:
Step a2: she cuts down to prepare the dehydrogenation shown in formula i using the preparation method any one of claim 1-6
Mine-laying is fixed；
Step b2: using the dehydrogenation Ivabradine shown in organic solvent dissolution type i, be subsequently adding organic acid, one-tenth is saltoutd
Crystalline substance, is filtrated to get the dehydrogenation Ivabradine acylate shown in formula iv；
Step c2: using the dehydrogenation Ivabradine acylate shown in methanol or ethanol dissolution type iv, then in palladium charcoal
There is hydrogenation reaction under catalyst action, reaction is filtered after terminating, and collects filtrate, evaporated under reduced pressure solvent, obtain her shown in formula v
Cut down mine-laying and determine acylate；
Step d2: be dissolved in water the Ivabradine acylate shown in formula v, adjusts ph value to 8～9, then uses acetic acid second
Ester is extracted, and separates organic faciess, and after washing with saturation metal complex agent solution and saturated nacl aqueous solution successively, separately has
After machine phase, drying and decolouring, filter, collect filtrate, evaporated under reduced pressure solvent, obtain Ivabradine.
Preferably, the organic solvent in described step b2 is selected from methanol, ethanol, acetonitrile, acetone or ethyl acetate；
Preferably, the organic acid in described step b2 is selected from oxalic acid, tartaric acid, malonic acid, lactic acid, acetic acid, acetone acid, richness
Horse acid, succinic acid, maleic acid, citric acid, methanesulfonic acid, benzenesulfonic acid or camphorsulfonic acid；It is highly preferred that described organic acid is selected from second
Acid, oxalic acid or tartaric acid；
Preferably, the metal chelating agent in described step d2 is selected from ammonia hydroxyl chelating agent, complexoness, ethylenediaminetetraacetic acid
One or more of disodium (edta-2na) or sulfydryl chelating agent.
Hereinafter technical scheme is described in detail.
By the present invention in that the compound shown in formula ii and the compound shown in formula iii occur nucleophilic substitution to be prepared into
To the intermediate dehydrogenation Ivabradine of Ivabradine, and then prepare Ivabradine.
Based on the compound shown in formula and the compound shown in formula all containing phenyl ring and diether linkage structure, inventor according to
" similar mix " principle carries out the design of phase transfer catalyst.Inventor carries out research and finds to conventional phase transfer catalyst:
When not using phase transfer catalyst, nucleophilic substitution is for up to 15.5h；Quaternary ammonium salt-type phase transfer catalyst is used as list
During one phase transfer catalyst, the response time can foreshorten to 9.5～13.0h, and catalytic effect is not ideal enough；Using polyethers phase transfer
When catalyst is as single phase transfer catalyst, the response time can foreshorten to 13.5～15.0h, and catalytic effect is not good；Crown ether-like
Phase transfer catalyst price costly, and has toxicity, to nucleophilic substitution no facilitation, no catalytic effect.
On the basis of single phase transfer catalyst result of study, inventor's sudden caprice, not good for catalytic effect is gathered
Ethers phase transfer catalyst and the dissatisfactory quaternary ammonium salt-type phase transfer catalyst of catalytic effect carry out compound use, and result is made us
Surprised: to add by quaternary ammonium salt-type phase transfer catalyst and polyethers phase transfer catalyst with answering that the mass ratio of 1～10:1 forms
(, as major catalyst, polyethers phase transfer catalyst is as co-catalysis for quaternary ammonium salt-type phase transfer catalyst to close phase transfer catalyst
Agent), nucleophilic substitution can be made to carry out in homogeneous, and so that the nucleophilic substitution time is contracted by more than the 15.0h of prior art
It is as short as 3.0-7.5h, reaction temperature is reduced to 80～85 DEG C by 90～100 DEG C of prior art, and the purity of product is carried
High.
Inventor carries out research to the nucleophilic substitution generating dehydrogenation Ivabradine and finds: the compound shown in formula
Reaction facile hydrolysiss produce hydroxyl impurity for a long time in the basic conditions, and hydroxyl impurity can produce solvation with anionic reactive reagent
Effect, makes reactivity reduce.Inventor utilizes complex phase transfer catalyst, and on the one hand becoming inhomogeneous reaction is homogeneous reaction,
Accelerate reaction rate, the hydrolysis of the compound shown in minimizing formula；Amino in another aspect quaternary ammonium salt-type phase transfer catalyst
With the hydroxyl in polyethers phase transfer catalyst, there is preferable intersolubility, significantly more reduce two alternate surface tension,
" plus and potentiation " effect can be played, further increase the conversion ratio of reaction.Quaternary ammonium salt-type phase transfer catalyst and polyethers phase
Complex phase transfer catalyst after transfer catalyst carries out compounding contains two kinds of catalytic active centers (polyether segment and quaternary ammoniums
Salt structure), the quaternary ammonium salt-type phase transfer catalyst that exists for of polyethers phase transfer catalyst provides a larger area of polarity
Domain, is conducive to the transfer to anion for the quaternary ammonium salt-type phase transfer catalyst；Meanwhile, polyethers phase transfer catalyst is as phase transfer
Catalyst can shift cation, thus being conducive to the carrying out of nucleophilic substitution with complex cation.
After the completion of nucleophilic substitution, used in the present invention, complex phase transfer catalyst is molten due to being dissolved in aprotic, polar
Agent and water, after filtering, complex phase transfer catalyst is transferred in filtrate reaction mother liquor, is divided by aqueous phase and organic extractant phase
Proceed to aqueous phase after layer and be removed.
The present invention is by being urged using the quaternary ammonium salt-type phase transfer catalyst being 1～10:1 by mass ratio and polyethers phase transfer
The complex phase transfer catalyst of agent composition, makes the yield of dehydrogenation Ivabradine of reaction generation and purity all be improved.
And the dehydrogenation Ivabradine being generated by nucleophilic substitution can not be directly used in catalytic hydrogenation and prepare Ivabradine, need
Purification process is carried out to it, dehydrogenation Ivabradine reaction being generated for this prior art carries out after column chromatography process,
Prepare Ivabradine for catalytic hydrogenation.Though column chromatography processes and can effectively remove impurity, high cost, organic solvent usage amount
Greatly, the difficulty for industrialization production is larger.And in the method for the invention, inventor pass through add organic acid formed dehydrogenation she
Cut down mine-laying and determine acylate, just can remove, through simple one-tenth salt crystallize, the hydroxyl impurity that molecular weight is that 277.0 contents are 5%～10%
With chiral isomer impurity, make the purity of dehydrogenation Ivabradine acylate reach more than 99.0%, and then generate through catalytic hydrogenation
Ivabradine acylate, then dissociates Ivabradine make it be dissolved in ethyl acetate with organic acid using in sig water
In, washed by saturation metal complex agent solution and remove metal ion, and adopt activated carbon adsorption coloring matter (decolouring), obtain
Highly purified Ivabradine, thus avoiding column chromatography procedure, greatly reducing the use of organic solvent, reducing and producing into
This, industrialization prospect is good, and the Ivabradine obtaining can meet the related request preparing hydrochloric acid Ivabradine crude drug.
The formation of emulsion layer in above-mentioned steps b1 and step d2, can be suppressed using saturated nacl aqueous solution, be conducive to improving
Extraction efficiency.Metal chelating agent can form stable water soluble complex with complexing of metal ion, makes the metal ion of organic faciess
It is extracted into aqueous phase, remove metal ion with the layering of organic faciess and aqueous phase.Inventor is studied by Experimental comparison and finds:
If not using saturation metal complex agent solution washing organic faciess, the heavy metal in hydrochloric acid Ivabradine product and residue on ignition difficult
To meet medicinal requirements.
Compared with prior art, the preparation method of the Ivabradine of the present invention and its intermediate at least have following beneficial
Effect:
First, the present invention passes through to add in nucleophilic substitution by quaternary ammonium salt-type phase transfer catalyst and polyethers phase transfer
Catalyst, with the complex phase transfer catalyst of the mass ratio composition of 1～10:1, significantly shorten the response time, and can reduce reaction
Temperature, reduces the generation of side reaction, improves the purity of dehydrogenation Ivabradine；
2nd, the present invention passes through to add organic acid to form dehydrogenation Ivabradine acylate and add saturation in the reaction
The process of metal chelating agent washing, can effectively remove metal ion, hydroxyl impurity and chiral isomer impurity etc., thus reducing gold
Belong to residual, it is to avoid column chromatography procedure, greatly reduce the use of organic solvent, improve dehydrogenation Ivabradine acylate
Purity, and then improve purity and the yield of Ivabradine, reduce production cost, be advantageously implemented the product of Ivabradine
Industry metaplasia produce, and the Ivabradine being obtained using the inventive method meet prepare hydrochloric acid Ivabradine crude drug correlation will
Ask；
3rd, the present invention is easier to obtain for the raw material preparing Ivabradine.
Brief description
Fig. 1 is the hplc figure about material for the dehydrogenation Ivabradine；
Fig. 2 is the hplc figure about material for the dehydrogenation Ivabradine oxalates；
Fig. 3 is the hplc figure about material for the Ivabradine.
Specific embodiment
Referring to specific embodiment, the present invention to be described.It will be appreciated by those skilled in the art that these embodiments are only
For the present invention is described, it limits the scope of the present invention never in any form.
Reagent material used in following embodiments, if no special instructions, is commercially available purchase product.
Embodiment 1The research of phase transfer catalyst
Inventor studies to conventional phase transfer catalyst (as shown in table 1).Using hplc(high performance liquid chromatography)
Method monitors the terminal of nucleophilic substitution, and the surpluses of the compound (wherein substituent group x is br) shown in when formula are less than 0.5%
When be considered as reaction completely.Experimental result is as shown in table 1, as seen from Table 1, when not using phase transfer catalyst, nucleophilic substitution
For up to 15.5h；Quaternary ammonium salt-type phase transfer catalyst using catalytic amount (the 2%～10% of compound quality shown in formula)
During as single phase transfer catalyst, serve certain catalytic action, the response time foreshortens to 9.5～13.0h, but catalysis effect
Fruit is still not ideal enough；Polyethers phase transfer catalyst using catalytic amount (the 2%～10% of compound quality shown in formula) is made
During for single phase transfer catalyst, the response time foreshortens to 13.5～15.0h, and catalytic effect is not good；Crown ether-like phase transfer catalysis
Agent price costly, and has toxicity, and the crown ether-like phase using catalytic amount (the 2%～10% of compound quality shown in formula) turns
Shifting catalyst is to nucleophilic substitution no facilitation, no catalytic effect.
The impact of the preparation to dehydrogenation Ivabradine for the different phase transfer catalyst of table 1
| Phase transfer catalyst | Response time | Purity | Molar yield (in terms of formula compound) |
| Benzyltriethylammoinium chloride | 11.5h | 85.05% | 98.3% |
| Benzyl triethyl ammonium bromide | 11.0h | 85.32% | 98.5% |
| Benzalkonium bromide | 9.5h | 86.10% | 99.2% |
| Benzyltrimethylammonium bromide | 11.5h | 85.37% | 98.8% |
| Tetrabutyl ammonium bromide | 12.5h | 84.22% | 99.0% |
| Tetrabutylammonium chloride | 13.0h | 83.26% | 98.9% |
| Polyethylene Glycol -200 | 13.5h | 83.38% | 98.1% |
| PEG-8 00 | 13.5h | 83.15% | 98.3% |
| Polyoxyethylene fatty alcohol | 14.5h | 81.42% | 97.0% |
| Polyoxyethylene alkylphenol | 15.0h | 81.73% | 97.7% |
| Hexaoxacyclooctadecane-6-6 | 15.0h | 80.55% | 98.2% |
| No | 15.5h | 80.62% | 98.0% |
, using quaternary ammonium salt-type phase transfer catalyst as major catalyst, polyethers phase transfer catalyst is as co-catalysis for inventor
Dosage form becomes complex phase transfer catalyst to be tested, and setting major catalyst is 5:1 with the mass ratio of promoter, compound phase transfer
The consumption of catalyst is the 5% of formula compound quality, and experimental result is as shown in table 2.As known from Table 2, by major catalyst with help
The compound use of catalyst, catalytic effect is much better than single phase transfer catalyst；Wherein, benzalkonium bromide and PEG-8 00
Compound use effect preferably, the response time foreshortens to 3.5h, the high purity 89.17% of dehydrogenation Ivabradine, molar yield
Reach 99.2%；Benzalkonium bromide and Polyethylene Glycol -200 compound use the reaction time also foreshorten to 3.5h, dehydrogenation Ivabradine
High purity 89.14%, molar yield reaches 99.2%.In addition, when major catalyst (quaternary ammonium salt-type phase transfer catalyst) is benzyl
When TEBA, benzyl triethyl ammonium bromide, benzalkonium bromide or benzyltrimethylammonium bromide, itself and different polyethers
Phase transfer catalyst (PEG-8 00, Polyethylene Glycol -200, polyoxyethylene fatty alcohol and polyoxyethylene alkylphenol) combines shape
Become complex phase transfer catalyst obtain preferably catalytic effect, the response time foreshortens to 3.5～7.0h, dehydrogenation she cut down mine-laying
Fixed purity reaches more than 86.35%, and molar yield reaches more than 97.3%.
The impact of the preparation to dehydrogenation Ivabradine for the different complex phase transfer catalyst of table 2
Inventor further to the major catalyst benzalkonium bromide in complex phase transfer catalyst and promoter Polyethylene Glycol-
800 mass ratio is investigated, and the consumption arranging complex phase transfer catalyst in experiment is the 5% of formula compound quality, real
Test result as shown in table 3.As known from Table 3, when the mass ratio of benzalkonium bromide and PEG-8 00 is 1:1, the response time just opens
Begin notable shorten, the quality of benzalkonium bromide is that 5 times of the reaction times of the quality of PEG-8 00 foreshorten to 3.5h, dehydrogenation she
Cut down the fixed high purity of mine-laying 89.28%, molar yield reaches 99.1%, and catalytic effect is optimal.Meanwhile, when the quality of benzalkonium bromide
When being respectively 3 times and 7 times of quality of PEG-8 00, the response time is also respectively shortened to 4.0h and 4.5h, dehydrogenation she cut down
The fixed purity of mine-laying is respectively 88.92% and 88.69%, and molar yield respectively reaches 98.5% and 98.7%, and catalytic effect is preferable.With
The increase further of benzalkonium bromide consumption, suppress acid binding agent to act on because it is attached on acid binding agent, make the response time not
Can shorten further, the purity of dehydrogenation Ivabradine then begins to decline；When the quality of benzalkonium bromide is PEG-8 00
When 10 times of quality, the response time increases to 7.5h, and the purity of dehydrogenation Ivabradine drops to less than 85.0%.Thus, originally
In invention setting complex phase transfer catalyst, the mass ratio of major catalyst and promoter is 1～10:1, preferably 3～7:1.
The impact of the preparation to dehydrogenation Ivabradine for the mass ratio of table 3 benzalkonium bromide and PEG-8 00
| Mass ratio | Response time | Purity | Molar yield (in terms of formula compound) |
| 1:3 | 13.0h | 84.04% | 98.3% |
| 1:2 | 12.0h | 84.35% | 99.1% |
| 1:1 | 7.5h | 87.10% | 98.6% |
| 3:1 | 4.0h | 88.92% | 98.5% |
| 5:1 | 3.5h | 89.28% | 99.1% |
| 7:1 | 4.5h | 88.69% | 98.7% |
| 10:1 | 7.5h | 84.85% | 98.6% |
Inventor on the basis of the mass ratio determining benzalkonium bromide and PEG-8 00 is 5:1, further to compound
The consumption of phase transfer catalyst is investigated, and result is as shown in table 4.As known from Table 4, the quality of complex phase transfer catalyst is
The quality of the compound shown in formula iii 4.0% when, the response time foreshortens to 3.0h, the high purity of dehydrogenation Ivabradine
89.35%, molar yield reaches 99.2%, and catalytic effect is optimal.When the quality of complex phase transfer catalyst is the change shown in formula iii
During the 2.0%-6.0% of the quality of compound, the response time foreshortens to below 4.5h, and the purity of dehydrogenation Ivabradine reaches 87.9%
More than, molar yield reaches more than 98.2%, and catalytic effect is preferable.Thus, the quality of the preferred complex phase transfer catalyst of the present invention
The 2.0%-6.0% of the compound quality shown in formula iii.
The impact of the preparation to dehydrogenation Ivabradine for the table 4 complex phase transfer catalyst consumption
Embodiment 2The preparation of dehydrogenation Ivabradine
In tri- mouthfuls of reaction bulbs of 500ml, by 20.0g formula iii compound dissolution in 200ml dmf, add 30.0g anhydrous
k2co3, stir 30 minutes, be subsequently adding 39.1g formula ii compound (wherein substituent group x is br), 0.8g complex phase transfer catalyst
(being mixed with the mass ratio of 5:l by benzalkonium bromide and PEG-8 00), reaction system is warming up to 85 DEG C, and hplc method is supervised
Measured reaction terminal, after reaction 3.0h, reaction is complete.Reaction finishes, cooling, filtrate is collected by filtration, filtrate is added and satisfies to 500ml
In sodium chloride solution, it is extracted twice with 250ml and 200ml ethyl acetate respectively, merges organic faciess, add the anhydrous na of 20g2so4
Be dried, filter, by filtrate at 50 DEG C concentrating under reduced pressure, obtain 37.9g dehydrogenation Ivabradine grease, purity be 89.29%,
The molar yield counted with formula iii compound is for 99.1%.Dehydrogenation Ivabradine is schemed as shown in figure 1, Fig. 1 about the hplc of material
In peak-data as shown in table 5.
Table 5 dehydrogenation Ivabradine is about the hplc figure peak-data of material
pda chl225nm4nm
| Peak # | Retention time | Area | Highly | Machine amasss % | Separating degree | Tailing factor | Theoretical tray # |
| 1 | 2.794 | 345994 | 38002 | 0.892 | 0.00 | 0.00 | 1986.5 |
| 2 | 3.238 | 176724 | 8715 | 0.456 | 1.12 | 0.00 | 578.2 |
| 3 | 4.209 | 12588 | 753 | 0.032 | 2.07 | 0.00 | 1786.7 |
| 4 | 4.999 | 25l724 | 17859 | 0.649 | 2.04 | 1.21 | 2811.1 |
| 5 | 6.365 | 20295 | 1039 | 0.052 | 3.15 | 0.00 | 2700.9 |
| 6 | 7.240 | 20144 | 804 | 0.052 | 1.48 | 1.56 | 1750.5 |
| 7 | 10.335 | 10494 | 428 | 0.027 | 4.50 | 0.00 | 3671.8 |
| 8 | 11.477 | 15034 | 518 | 0.039 | 0.12 | 0.00 | 6.1 |
| 9 | 13.082 | 34621100 | 922060 | 89.285 | 0.16 | 2.01 | 2789.9 |
| 1o | 15.801 | 2951785 | 92782 | 7.612 | 2.96 | 1.05 | 5603.4 |
| 11 | 17.498 | 91848 | 1212 | 0.237 | 1.03 | 0.00 | 816.8 |
| 12 | 24.101 | 48632 | 898 | 0.125 | 3.35 | 1.07 | 4174.4 |
| 13 | 37.113 | 59261 | 1935 | 0.153 | 11.16 | 1.00 | 31313.5 |
| l4 | 41.383 | 136107 | 5722 | 0.351 | 5.80 | 1.13 | 68269.5 |
| 15 | 48.456 | 14282 | 569 | 0.037 | 10.81 | 0.93 | 82545.6 |
| Amount to | 38776010 | 1093296 | 100.000 |
Embodiment 3The preparation of dehydrogenation Ivabradine
In tri- mouthfuls of reaction bulbs of 500ml, by 20.0g formula iii compound dissolution in 200ml dmf, add 23.0g anhydrous
na2co3, stir 30 minutes, be subsequently adding 27g formula ii compound (wherein substituent group x is c1), 0.6g complex phase transfer catalyst
(being mixed with the mass ratio of 7:l by benzalkonium bromide and Polyethylene Glycol -200), reaction system is warming up to 80 DEG C, and hplc method is supervised
Measured reaction terminal, after reaction 4.5h, reaction is complete.Reaction finishes, cooling, filtrate is collected by filtration, filtrate is added and satisfies to 500ml
In sodium chloride solution, it is extracted twice with 250ml and 200ml ethyl acetate respectively, merges organic faciess, add the anhydrous na of 20g2so4
Be dried, filter, by filtrate at 50 DEG C concentrating under reduced pressure, obtain 37.7g dehydrogenation Ivabradine grease, purity be 88.39%,
The molar yield counted with formula iii compound is for 98.4%.
Embodiment 4The preparation of dehydrogenation Ivabradine
In tri- mouthfuls of reaction bulbs of 500ml, by 20g formula iii compound dissolution in 200ml dmso, add 30.0g anhydrous
k2co3, stir 30 minutes, be subsequently adding 44.5g formula ii compound (wherein substituent group x is br), 1.2g complex phase transfer catalyst
(being mixed with the mass ratio of 3:l by benzyltriethylammoinium chloride and polyoxyethylene alkylphenol), reaction system is warming up to 85
DEG C, hplc method monitors reaction end, and after reaction 5h, reaction is complete.Reaction finishes, cooling, filtrate is collected by filtration, filtrate is added
To 500ml saturated nacl aqueous solution, it is extracted twice with 250ml and 200ml ethyl acetate respectively, merges organic faciess, add 20g
Anhydrous na2so4Be dried, filter, by filtrate at 50 DEG C concentrating under reduced pressure, obtain 37.9g dehydrogenation Ivabradine grease, purity
For 88.17%, the molar yield counted with formula iii compound is for 99.1%.
Embodiment 5The preparation of Ivabradine
1st, the preparation of dehydrogenation Ivabradine oxalates
The dehydrogenation Ivabradine grease 37.8g of Example 2 preparation, adds 200ml ethanol, stirring, is slowly added into
10.0g bis- oxalic acid hydrate, becomes salt 30min, crystallize 2h under room temperature, filters, is drying to obtain 37.4g dehydrogenation Ivabradine oxalic acid
Salt, purity is 99.54%, and molar yield is 77.9%.Dehydrogenation Ivabradine oxalates are schemed as Fig. 2 institute about the hplc of material
Show, the peak-data in Fig. 2 is as shown in table 6.
Table 6 dehydrogenation Ivabradine oxalates are about the hplc figure peak-data of material
pda chl225nm4nm
| Peak # | Retention time | Area | Highly | Machine amasss % | Separating degree | Tailing factor | Theoretical tray # |
| 1 | 2.783 | 12159 | 1199 | 0.064 | 0.00 | 1.20 | 1550.0 |
| 2 | 13.300 | 18774320 | 524750 | 99.536 | 17.14 | 1.75 | 3174.2 |
| 3 | 15.834 | 54754 | 1595 | 0.290 | 2.75 | 0.00 | 4998.6 |
| 4 | 41.457 | 20515 | 884 | 0.109 | 33.52 | 1.05 | 68633.0 |
| Amount to | 18861748 | 528428 | 100.000 |
2nd, the preparation of Ivabradine
The dehydrogenation Ivabradine oxalates 37.2g taking above-mentioned preparation is dissolved in 200ml methanol, is transferred to high-pressure hydrogenation
In reactor, add 4.0g 1o% mass fraction palladium carbon catalyst under 35～40 DEG C, 1～4atm pressure hydrogenation reaction
Llh, filters after reaction, and filter cake is washed with a small amount of methanol, reclaims palladium carbon catalyst, evaporated under reduced pressure is molten at 40～45 DEG C by filtrate
Agent obtains Ivabradine oxalates.It is subsequently adding 400ml purified water, so that Ivabradine oxalates is dissolved completely, use 1o%
The naoh solution of mass fraction adjusts ph value to 8.5, adds 400ml ethyl acetate, stratification after stirring, by organic faciess according to
Secondary 200ml saturation edta-2na solution and 200ml saturated nacl aqueous solution wash, layering, collect organic faciess, add 20g no
Aqueous sodium persulfate is dried, and adds 0.4g activated carbon decolorizing 30min, filters, filtrate is evaporated in 50 DEG C dry, obtains
24.2g Ivabradine highly finished product, purity is 97.29%, and molar yield is 82.3%.Ivabradine is about the hplc of material
Figure is as shown in figure 3, the peak-data in Fig. 3 is as shown in table 7.
Table 7 Ivabradine is about the hplc figure peak-data of material
pda chl225nm4nm
| Peak # | Retention time | Area | Highly | Area % | Theoretical tray # | Separating degree | Tailing factor |
| 1 | 2.898 | 65759 | 4570 | 1.133 | 930.900 | 0.000 | 0.00 |
| 2 | 3.253 | 23747 | 1689 | 0.409 | 10.076 | 0.159 | 0.00 |
| 3 | 3.445 | 24810 | 1533 | 0.427 | 15.414 | 0.051 | 0.00 |
| 4 | 3.988 | 5419 | 314 | 0.093 | 836.584 | 0.267 | 0.00 |
| 5 | 4.456 | 5648837 | 384391 | 97.293 | 2067.063 | 0.990 | 1.43 |
| 6 | 5.320 | 17516 | l028 | 0.302 | 2440.497 | 2.100 | 1.49 |
| 7 | 6.031 | 5773 | 229 | 0.099 | 1383.739 | 1.319 | 1.52 |
| 8 | 7.076 | 9878 | 513 | 0.170 | 3000.404 | 1.793 | 1.14 |
| 9 | 7.918 | 4286 | 221 | 0.074 | 3540.034 | 1.605 | l.25 |
| Amount to | 5806024 | 394487 | 100.000 |
Embodiment 6The preparation of Ivabradine
1st, the preparation of dehydrogenation Ivabradine tartrate
The dehydrogenation Ivabradine grease 37.6g of Example 3 preparation, adds 200ml acetone, stirring, is slowly added into
15.0g mono- is hydrated dl- tartaric acid, becomes salt 30min, crystallize 4h under room temperature, filters, is drying to obtain 38.7g dehydrogenation Ivabradine
Tartrate, purity is 99.34%, and molar yield is 75.3%.
2nd, the preparation of Ivabradine
The dehydrogenation Ivabradine tartrate 38.6g taking above-mentioned preparation is dissolved in 200ml methanol, is transferred to high pressure and adds
In hydrogen reactor, add 4.0g10% mass fraction palladium carbon catalyst under 35～40 DEG C, l～4atm pressure hydrogenation reaction
Llh, filters after reaction, and filter cake is washed with a small amount of methanol, reclaims palladium carbon catalyst, evaporated under reduced pressure is molten at 40～45 DEG C by filtrate
Agent obtains Ivabradine tartrate.It is subsequently adding 400ml purified water, so that Ivabradine tartrate is dissolved completely, use
The naoh solution of lo% mass fraction adjusts ph value to 8, adds 400ml ethyl acetate, stratification after stirring, by organic faciess
Washed with 200ml saturation edta-2na solution and 200ml saturated nacl aqueous solution successively, layering, collect organic faciess, add 20g
Anhydrous sodium sulfate drying, adds 0.4g activated carbon decolorizing 30min, filters, filtrate is evaporated in 50 DEG C dry, obtains
23.2g Ivabradine highly finished product, purity is 97.24%, and molar yield is 81.3%.
Embodiment 7The preparation of Ivabradine
1st, the preparation of dehydrogenation Ivabradine acetate
The dehydrogenation Ivabradine grease 37.8g of Example 4 preparation, adds 180ml ethyl acetate, stirs, slowly
Add 5.4g acetic acid, under room temperature, become salt 30min, crystallize 8h, filter, be drying to obtain 32.7g dehydrogenation Ivabradine acetate, pure
Spend for 99.37%, molar yield is 76.6%.
2nd, the preparation of Ivabradine
The dehydrogenation Ivabradine acetate 32.7g taking above-mentioned preparation is dissolved in 200ml ethanol, is transferred to high-pressure hydrogenation
In reactor, add 4.0g10% mass fraction palladium carbon catalyst under 35～40 DEG C, 1～4atm pressure hydrogenation reaction 11h,
Filter after reaction, a small amount of washing with alcohol of filter cake, reclaim palladium carbon catalyst, evaporated under reduced pressure solvent obtains at 40～45 DEG C by filtrate
To Ivabradine acetate.It is subsequently adding 400ml purified water, so that Ivabradine acetate is dissolved completely, divided with 10% mass
The naoh solution of number adjusts ph value to 9, adds 400ml ethyl acetate, and organic faciess are used by stratification successively after stirring
200ml saturated ammonia hydroxyl enveloping agent solution and the washing of 200ml saturated nacl aqueous solution, layering, collect organic faciess, add 20g anhydrous
Sodium sulfate is dried, and adds 0.4g activated carbon decolorizing 30min, filters, filtrate is evaporated in 50 DEG C dry, obtains 23.4g
Ivabradine highly finished product, purity is 97.17%, and molar yield is 80.8%.
Specific description of embodiments of the present invention above is not intended to limit the present invention, and those skilled in the art can be according to this
Invention is variously modified or deforms, and without departing from the spirit of the present invention, all should belong to the model of claims of the present invention
Enclose.
Claims (17)
1. a kind of preparation method of dehydrogenation Ivabradine is it is characterised in that include:
Step a1: make the compound shown in formula ii and the compound shown in formula iii in acid binding agent and complex phase transfer catalyst
In the presence of in polar non-solute occur nucleophilic substitution generate dehydrogenation Ivabradine；
Step b1: the dehydrogenation Ivabradine obtaining in step a1 is carried out with separation, purification；
Wherein, described complex phase transfer catalyst is 1～10:1 by mass ratio quaternary ammonium salt-type phase transfer catalyst and polyethers
Phase transfer catalyst forms, and described x is selected from cl, br, i, sulfonyloxy；Described quaternary ammonium salt-type phase transfer catalyst is selected from benzyl three
Ethyl ammonium chloride, benzyl triethyl ammonium bromide, benzalkonium bromide or benzyltrimethylammonium bromide；Described polyethers phase transfer catalyst
For Polyethylene Glycol.
2. preparation method according to claim 1 is it is characterised in that the preparation method bag of described dehydrogenation Ivabradine
Include:
Step a1: make the compound shown in formula ii and the compound shown in formula iii in acid binding agent and complex phase transfer catalyst
In the presence of in polar non-solute occur nucleophilic substitution generate dehydrogenation Ivabradine；
Step b1: the dehydrogenation Ivabradine obtaining in step a1 is carried out with separation, purification；
Wherein, described complex phase transfer catalyst is 1～10:1 by mass ratio quaternary ammonium salt-type phase transfer catalyst and polyethers
Phase transfer catalyst forms, and described x is selected from cl, br, i, sulfonyloxy methyl epoxide, phenylsulfonyloxy, tolysulfonyl epoxide, adjacent first
Phenylsulfonyloxy or a tosyloxy；Described quaternary ammonium salt-type phase transfer catalyst is selected from benzyltriethylammoinium chloride, benzyl
Triethylammonium bromide, benzalkonium bromide or benzyltrimethylammonium bromide；Described polyethers phase transfer catalyst is Polyethylene Glycol.
3. preparation method according to claim 1 and 2 is it is characterised in that described quaternary ammonium salt-type phase transfer catalyst is benzene
Prick bromine ammonium.
4. preparation method according to claim 1 and 2 is it is characterised in that described polyethers phase transfer catalyst is molecule
Polyethylene Glycol between 200～800 for the amount.
5. preparation method according to claim 1 and 2 is it is characterised in that the consumption of described complex phase transfer catalyst is
2.0%～6.0% of compound quality shown in formula.
6. preparation method according to claim 1 and 2 is it is characterised in that the consumption of described complex phase transfer catalyst is
4.0% of compound quality shown in formula.
7. preparation method according to claim 1 and 2 is it is characterised in that in described complex phase transfer catalyst, described season
The mass ratio of ammonium salt class phase transfer catalyst and described polyethers phase transfer catalyst is 3～7:1.
8. preparation method according to claim 1 and 2 is it is characterised in that in described complex phase transfer catalyst, described season
The mass ratio of ammonium salt class phase transfer catalyst and described polyethers phase transfer catalyst is 5:1.
9. preparation method according to claim 1 and 2 it is characterised in that described acid binding agent be selected from sodium carbonate, potassium carbonate,
Potassium bicarbonate or sodium bicarbonate；Described polar non-solute is selected from dimethylformamide, dimethyl acetylamide, dimethyl sulfoxide
Or acetonitrile.
10. preparation method according to claim 1 and 2 is it is characterised in that the nucleophilic substitution in described step a1 exists
Carry out at 80-85 DEG C.
11. preparation methoies according to claim 1 and 2 are it is characterised in that described step b1 includes: the change shown in formula ii
After compound is reacted with the compound shown in formula iii, cooling, filter, collect filtrate, filtrate is added in saturated nacl aqueous solution,
Extracted with ethyl acetate, separate organic faciess, after concentrating under reduced pressure, obtain dehydrogenation Ivabradine.
A kind of 12. preparation methoies of Ivabradine are it is characterised in that the preparation method of described Ivabradine includes following step
Rapid:
Step a2: dehydrogenation Ivabradine is prepared using the preparation method any one of claim 1-11；
Step b2: dissolve described dehydrogenation Ivabradine, and dehydrogenation Ivabradine acylate is obtained by salt-forming reaction；
Step c2: dissolve described dehydrogenation Ivabradine acylate, Ivabradine acylate is obtained by hydrogenation reaction；
Step d2: dissolve described Ivabradine acylate, obtain her after adjusting ph value, extraction, separation, washing and cut down mine-laying
Fixed.
13. preparation methoies according to claim 12 it is characterised in that the preparation method of described Ivabradine include with
Lower step:
Step a2: dehydrogenation Ivabradine is prepared using the preparation method any one of claim 1-11；
Step b2: described dehydrogenation Ivabradine is dissolved using organic solvent, is subsequently adding organic acid, become salt crystallize, filter
To dehydrogenation Ivabradine acylate；
Step c2: described dehydrogenation Ivabradine acylate is dissolved using methanol or ethanol, then acts in palladium carbon catalyst
Lower generation hydrogenation reaction, reaction is filtered after terminating, and collects filtrate, evaporated under reduced pressure solvent, obtains Ivabradine acylate；
Step d2: be dissolved in water described Ivabradine acylate, adjusts ph value to 8～9, is then extracted with ethyl acetate
Take, separate organic faciess, and after washing with saturation metal complex agent solution and saturated nacl aqueous solution successively, separately organic faciess, warp
After being dried and decolouring, filter, collect filtrate, evaporated under reduced pressure solvent, obtain Ivabradine.
14. preparation methoies according to claim 13 are it is characterised in that the organic solvent in described step b2 is selected from first
Alcohol, ethanol, acetonitrile, acetone or ethyl acetate.
15. preparation methoies according to claim 13 it is characterised in that organic acid in described step b2 be selected from oxalic acid,
Tartaric acid, malonic acid, lactic acid, acetic acid, acetone acid, fumaric acid, succinic acid, maleic acid, citric acid, methanesulfonic acid, benzenesulfonic acid or Camphor tree
Brain sulfonic acid.
16. preparation methoies according to claim 13 it is characterised in that organic acid in described step b2 be selected from acetic acid,
Oxalic acid or tartaric acid.
17. preparation methoies according to claim 13 are it is characterised in that the metal chelating agent in described step d2 is selected from ammonia
One or more of hydroxyl chelating agent, complexoness, disodiumedetate or sulfydryl chelating agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310432959.8A CN104447553B (en) | 2013-09-22 | 2013-09-22 | Preparation method for ivabradine and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310432959.8A CN104447553B (en) | 2013-09-22 | 2013-09-22 | Preparation method for ivabradine and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104447553A CN104447553A (en) | 2015-03-25 |
| CN104447553B true CN104447553B (en) | 2017-02-01 |
Family
ID=52894383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310432959.8A Active CN104447553B (en) | 2013-09-22 | 2013-09-22 | Preparation method for ivabradine and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447553B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727266A (en) * | 2017-04-18 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of Ivabradine impurity |
| CN107698508B (en) * | 2017-10-24 | 2021-01-05 | 重庆东得医药科技有限公司 | Synthesis method of dehydroivabradine |
| CN108424390A (en) * | 2018-01-25 | 2018-08-21 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity hydrochloric acid Ivabradine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN102264689A (en) * | 2008-12-22 | 2011-11-30 | 新梅斯托克尔卡公司 | Process for preparation of ivabradine |
| CN102498102A (en) * | 2009-09-18 | 2012-06-13 | 瑟维尔实验室 | Novel method for synthesizing ivabradine and the addition salts thereof with a pharmaceutically acceptable acid |
| CN102633720A (en) * | 2011-02-14 | 2012-08-15 | 瑟维尔实验室 | New method for synthesising ivabradine and its added salts with a pharmaceutically acceptable acid. |
| CN103012268A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel preparation method for ivabradine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2528026T3 (en) * | 2007-05-30 | 2015-02-03 | Ind-Swift Laboratories Limited | Salts of crystalline ivabridine oxalate and polymorphs thereof |
-
2013
- 2013-09-22 CN CN201310432959.8A patent/CN104447553B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN102264689A (en) * | 2008-12-22 | 2011-11-30 | 新梅斯托克尔卡公司 | Process for preparation of ivabradine |
| CN102498102A (en) * | 2009-09-18 | 2012-06-13 | 瑟维尔实验室 | Novel method for synthesizing ivabradine and the addition salts thereof with a pharmaceutically acceptable acid |
| CN102633720A (en) * | 2011-02-14 | 2012-08-15 | 瑟维尔实验室 | New method for synthesising ivabradine and its added salts with a pharmaceutically acceptable acid. |
| CN103012268A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel preparation method for ivabradine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104447553A (en) | 2015-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105622609B (en) | A kind of Li Gelieting preparation method | |
| CN108947891B (en) | Method for safely preparing pimavanserin and tartrate thereof by using triphosgene | |
| AU2018294254B2 (en) | Synthesis of omecamtiv mecarbil | |
| CN101006064B (en) | Method for preparing irbesartan and intermediates thereof | |
| CN104447553B (en) | Preparation method for ivabradine and intermediate thereof | |
| CN103073438B (en) | Ambroxol hydrochloride compound refining method | |
| CN102040606A (en) | Synthetic method of vinpocetine | |
| CN104447554B (en) | Preparation method for ivabradine and hydrochloride thereof | |
| CN108178751A (en) | A kind of synthetic method of the net intermediates of En Gelie | |
| CN103012382B (en) | A kind of preparation method of olmesartan medoxomil | |
| CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
| CN104761555A (en) | Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method | |
| CN108059601A (en) | A kind of technique for preparing 3- amino-1-adamantane alcohols | |
| CN111548306B (en) | Purification method of cisatracurium besilate | |
| CN103224469A (en) | Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof | |
| CN104311467B (en) | Pipe reaction continuously prepares the method and device of vildagliptin | |
| CN103159633A (en) | Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride | |
| CN108084145B (en) | Ticagrelor intermediate and preparation method thereof | |
| CN105949184B (en) | Refining method of arotinolol hydrochloride | |
| CN106117104B (en) | A kind of preparation method of vildagliptin | |
| CN114262320A (en) | Synthesis method for preparing anilinopiperidine drugs by using continuous flow microchannel reactor | |
| CN111484424B (en) | Method for synthesizing omacycline | |
| CN101606976B (en) | Method for preparing tetrandrine alkaloids by coupling in-situ conversion-adsorptive separation technology | |
| CN105037245B (en) | Saxagliptin midbody preparing method | |
| CN102219779A (en) | Method for synthetizing irbesartan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |