CN108101841B - Method for preparing indacaterol or salt thereof - Google Patents
Method for preparing indacaterol or salt thereof Download PDFInfo
- Publication number
- CN108101841B CN108101841B CN201711181431.2A CN201711181431A CN108101841B CN 108101841 B CN108101841 B CN 108101841B CN 201711181431 A CN201711181431 A CN 201711181431A CN 108101841 B CN108101841 B CN 108101841B
- Authority
- CN
- China
- Prior art keywords
- salt
- compound
- formula
- acid
- indacaterol
- 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
- 238000000034 method Methods 0.000 title claims abstract description 31
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 title claims abstract description 18
- 229960004078 indacaterol Drugs 0.000 title claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 150000004678 hydrides Chemical class 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
- 238000007142 ring opening reaction Methods 0.000 claims description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 239000011976 maleic acid Substances 0.000 claims description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 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 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 235000010233 benzoic acid Nutrition 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
- 239000001530 fumaric acid Substances 0.000 claims description 2
- HLANOUYSOJLOPM-UHFFFAOYSA-N methoxy benzenesulfonate Chemical compound COOS(=O)(=O)C1=CC=CC=C1 HLANOUYSOJLOPM-UHFFFAOYSA-N 0.000 claims description 2
- UJJUJHTVDYXQON-UHFFFAOYSA-N nitro benzenesulfonate Chemical compound [O-][N+](=O)OS(=O)(=O)C1=CC=CC=C1 UJJUJHTVDYXQON-UHFFFAOYSA-N 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims 1
- IREJFXIHXRZFER-PCBAQXHCSA-N indacaterol maleate Chemical compound OC(=O)\C=C/C(O)=O.N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 IREJFXIHXRZFER-PCBAQXHCSA-N 0.000 abstract description 6
- 229960004735 indacaterol maleate Drugs 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 15
- -1 alkyl acetates Chemical class 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005086 pumping Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- KGVIJLMNQNSQHB-UHFFFAOYSA-N 5,6-diethyl-2,3-dihydro-1h-inden-2-amine Chemical compound C1=C(CC)C(CC)=CC2=C1CC(N)C2 KGVIJLMNQNSQHB-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for preparing indacaterol or a salt thereof. Specifically, the method selects hydrogen diluted by inert gas as a hydride source to prepare the high-purity indacaterol maleate under the condition of metal catalysis.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to an improved preparation method of indacaterol or a salt thereof.
Background
Indacaterol maleate is a bronchodilatory active β -selective adrenoceptor agonist developed by novartis, useful in the treatment of asthma and chronic obstructive pulmonary disease, and has a very long duration of action in vitro and in vivo.
Indacaterol maleate is chemically known as 5- [ (1R) -2- [ (5, 6-diethyl-2, 3-dihydro-1H-indan-2-yl) amino ] -1-hydroxyethyl ] -8-hydroxy-1H-quinolin-2-one maleate and has the following structural formula:
methods for the synthesis of indacaterol are disclosed in the prior art. For example, in the methods reported in patents US6878721, WO200476422, WO2005123684, etc., the compound 8-benzyloxy-5- (R) -oxiranyl- (1H) -quinolin-2-one reacts with 5, 6-diethyl-2, 3-dihydro-1H-inden-2-amine to obtain an intermediate, and the indacaterol is obtained by removing the benzyl protecting group, and the reaction route is as follows:
in the process of removing the benzyl protecting group, the compound 3 is easily over-hydrogenated to generate the impurity A, and the impurity is difficult to remove by conventional purification means, such as column chromatography or recrystallization. The process conditions are to be further optimized.
Therefore, research and development on a process for preparing indacaterol or a salt thereof are required.
The invention provides a method for preparing indacaterol or salt thereof, which can effectively inhibit the generation of impurity A, and the obtained product is easy to purify and suitable for industrial production.
Disclosure of Invention
The present invention provides a process for preparing indacaterol or a salt thereof, the process comprising: subjecting the compound of formula II or a salt thereof to a catalytic hydrogenation reaction under the condition of a metal catalyst/hydride source to obtain the compound of formula I, indacaterol or a salt thereof,
wherein R is1Is a hydroxy protecting group, R2The hydride source is a hydrogen-containing mixed gas in order to avoid over-hydrogenation of the compound of formula I, wherein the content of hydrogen in the mixed gas is not higher than 90% (V/V), preferably 40-80% (V/V), and specifically may be 40, 45, 50, 55, 60, 65, 70, 75, 80%, more preferably 50-75% (V/V); the hydrogen-containing mixed gas is prepared by mixing high-purity hydrogen with inert gas, such as nitrogen and argon, which is well known to those skilled in the art; the metal catalyst used for the catalytic hydrogenation reaction is well known to those skilled in the art, and is preferably at least one selected from palladium on carbon, palladium hydroxide, platinum oxide, palladium on alumina, platinum on activated carbon and Raney nickel, and more preferably palladium on carbon, palladium hydroxide.
In the embodiment of the present invention, the amount of the metal catalyst used in the catalytic hydrogenation reaction is 1 to 20% (by mass, calculated as the mass of the compound of formula II), specifically 1,2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% (by mass), and preferably 5 to 10% (by mass); the molar concentration of the materials in the reaction is 0.1-2M (calculated by the molar concentration of the compound in the organic solvent, shown as the formula II), and preferably 0.1-1.25M.
The palladium-carbon used in the invention contains 1-20% (by mass) of palladium, specifically 5%, 10% and 15%.
The solvent (first solvent) used in the catalytic hydrogenation reaction of the present invention is selected from alkyl acetates, such as ethyl acetate; alcohols, e.g. C1-6Alkyl alcohols such as methanol, ethanol, propanol, butanol and pentanol; aliphatic C6-12A hydrocarbon; dimethylformamide; aromatic hydrocarbons such as toluene and benzene; acetonitrile; heterocycles, such as tetrahydrofuran; a dialkyl ether; dimethyl sulfoxide; dialkyl carbonates, such as dimethyl carbonate; acids, such as acetic acid, trifluoroacetic acid; aqueous solvents, such as water; an ionic liquid; chlorinated solvents, such as dichloromethane. Mixtures of solvents may also be used. Preferably at least one of ethyl acetate, methanol, ethanol, propanol, butanol, pentanol, N-dimethylformamide, toluene, benzene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, acetic acid, trifluoroacetic acid, water, dichloromethane, more preferably at least one of methanol, ethanol, propanol, butanol, pentanol, acetic acid, trifluoroacetic acid.
The temperature of the catalytic hydrogenation reaction is preferably 0-70 ℃, preferably 10-50 ℃, and more preferably 10-30 ℃.
In a specific embodiment of the invention, the hydroxy protecting group (R)1) Is benzyl having the formula:
in a specific embodiment of the invention, the hydroxy protecting group (R)1) For benzyl, said amino-protecting group (R)2) Is benzyl having the formula:
in a preferred embodiment of the present invention, the hydroxyl protecting group (R)1) For benzyl, said amino-protecting group (R)2) Is hydrogen, having the formula:
the compound salt of the formula II is tosylate, methoxybenzenesulfonate or nitrobenzenesulfonate, and is preferably tosylate.
Further, in a solvent, the compound of formula III and the compound of formula IV undergo an epoxy ring-opening reaction (ring-opening reaction for short) to produce the compound of formula II.
The solvent used in the ring-opening reaction is selected from dimethyl sulfoxide, N-dimethylformamide, acetonitrile, N-methylpyrrolidone or C3-C6Preferably dimethyl sulfoxide, N-dimethylformamide; the temperature used in the ring-opening reaction is 10-160 ℃, preferably 50-140 ℃, and more preferably 80-120 ℃.
Wherein R is1、R2As defined above.
In a preferred embodiment the amino protecting group is benzyl and the compound of formula IV has the formula:
researchers take the compound 2B to participate in the epoxy ring-opening reaction to obtain the corresponding compound shown in the formula II, the method can reduce the generation of impurities B and C, reduce the workload of subsequent purification, improve the yield of the whole synthetic route and the utilization rate of the compound shown in the formula III,
the invention also provides a preparation method of the indacaterol salt, which comprises the step of reacting the compound of the formula II obtained by the catalytic hydrogenation reaction with a corresponding acid in a solvent (a second solvent) to obtain the indacaterol salt, preferably the indacaterol maleate.
The second solvent of the present invention may be, but is not limited to, at least one of methanol, ethanol, propanol, butanol, amyl alcohol ethyl acetate, and dichloromethane; the acid is selected from benzoic acid, maleic acid, succinic acid, fumaric acid and tartaric acid, and is preferably maleic acid.
The invention also provides the indacaterol or the pharmaceutically acceptable salt thereof prepared by the method.
The present invention also provides a drug substance comprising indacaterol or a salt thereof, wherein the content of impurity a is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, most preferably less than 0.1%, for example less than 0.09%, 0.08%, 0.07% or 0.06% of impurity a. It is to be understood that the content of impurity a here is a content value determined by HPLC.
The "hydroxyl-protecting group" or "amino-protecting group" according to the present invention is a group known in the art to be suitably used for hydroxyl protection, see hydroxyl-protecting Groups in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.green & p.g.m.wuts). Illustratively, the hydroxyl or amino protecting group, together with the oxygen or nitrogen atom to which it is bound, is preferably benzyl (Bn), p-methoxybenzyl, 2,4, 6-trimethoxybenzyl, Methoxyethoxymethyl Ether (MEM), trityl (Tr), Dimethoxytrityl (DMT), methoxymethyl ether (MOM), or the like, to form an alkyl ether.
Detailed description of the invention
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group selected from alkyl groups containing 1 to 6 carbon atoms (which may be described as C)1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl.
The sample detection method (HPLC) of the present invention is as follows:
a chromatographic column: YMC-Pack ODS-AQ (5 μm 150X 4.6 mm); wavelength: 210 nm; mobile phase: water/acetonitrile, phosphate as buffer.
The reagents according to the invention are commercially available and are prepared by the methods described in the intermediates referred to in WO2004076422 or WO 2000075114.
Detailed Description
The present invention will be explained in detail with reference to specific examples below, so that those skilled in the art can more fully understand the specific examples of the present invention to illustrate the technical solutions of the present invention, and not to limit the present invention in any way.
Example 1:
dissolving a compound 3a (100g, prepared according to the method in the patent WO 2000075114) in methanol (2L), adding a 5% palladium carbon catalyst (wet., 5g), pumping gas for 2 times by using a hydrogen-nitrogen mixed gas (70% V/V hydrogen), charging the hydrogen-nitrogen mixed gas, stirring for reaction for 17-18 hours, detecting the reaction completion by TLC, filtering to remove the catalyst, adding 100mL of a methanol solution of maleic acid (26g) into the obtained mother liquor, removing a part of the solvent (1.5L) by decompression, adding 2L of ethanol, stirring, and filtering to obtain 93g of indacaterol maleate, wherein the yield is 88%, the HPLC purity is 99%, and the impurity A is 0.06%.
1HNMR(BRUKER-400MHz,DMSO-d6)δ9.02(s,2H),8.19-8.16(d,1H),7.21-7.19(d,1H),7.03(s,2H),7.02-7.00(d,1H),6.62-6.60(d,1H),6.23(s,1H),6.04(s,2H),5.36-5.33(m,1H),4.12-4.04(m,1H),3.28-3.00(m,6H),2.59-2.54(q,4H),1.15-1.11(t,6H).
Example 2:
dissolving a compound 3a (100g) in methanol (2L), adding a 5% palladium carbon catalyst (wet., 5g), pumping gas for 2 times by using hydrogen, filling the hydrogen, stirring the mixture to react for 17-18 hours, detecting the reaction completion by TLC, filtering the mixture to remove the catalyst, adding 100mL of methanol solution of maleic acid (26g) into the obtained mother liquor, decompressing and spinning off part of the solvent (1.5L), adding 2L of ethanol, pulping, filtering, and blowing and drying the mixture for 5 hours at 50 ℃ to obtain 90g of indacaterol maleate, wherein the yield is 88%, the HPLC purity is 99%, and the impurity A is 0.5%.
Example 3: preparation of maleate salt of impurity A
Dissolving the compound 3a (5g) in methanol (2L), adding 10% palladium carbon catalyst (wet., 5g), pumping gas for 2 times by using hydrogen, filling hydrogen, stirring for reaction, filtering to remove the catalyst, concentrating to dryness, and purifying by column chromatography to obtain an impurity A crude product. The crude product of impurity A was dissolved in 100mL of absolute ethanol, 10mL of ethanol solution of maleic acid (0.5g) was added, the mixture was heated at 50 ℃ for 30 minutes, part of the solvent (70mL) was removed under reduced pressure, and the mixture was filtered and dried by blowing at 50 ℃ for 5 hours to obtain 1g of maleate salt of impurity A, the HPLC purity was 99%.
1HNMR(BRUKER-400MHz,DMSO-d6)δ9.86(s,1H),8.96(s,2H),8.77(s,1H),7.02(s,2H),7.00(d,1H),6.78-6.76(d,1H),6.04(s,2H),5.99(d,1H),5.04-5.01(m,1H),4.1-4.0(m,1H),3.3-2.8(m,8H),2.7-2.3(m,6H),1.2-1.1(t,6H).
Example 4:
the conditions for the selection of hydrodebenzylation by catalytic hydrogenation described above with reference to example 1: dissolving the compound 3a (0.5g) in methanol (30mL), adding a catalyst and a hydride source, stirring to react completely, directly sampling for HPLC central control detection, wherein specific data are shown as follows:
TABLE 1
From the data of the above experimental examples, it can be easily found that the generation of the impurity a by over-hydrogenation during the reaction can be effectively controlled by selecting 60% (V/V) or 70% (V/V) hydrogen as the hydride source, and the generation of the impurity is not related to the kind of the catalyst, the amount of the catalyst, the activity of the catalyst and the amount of the catalyst containing different palladium.
Claims (16)
1. A process for the preparation of indacaterol or a salt thereof, comprising catalytically hydrogenating a compound of formula II or a salt thereof in the presence of a metal catalyst/hydride source to obtain indacaterol or a salt thereof, wherein R is1Is a hydroxy protecting group, R2Is a hydrogen or an amino protecting group,
the method is characterized in that the hydride source is mixed gas with the hydrogen content of 40-80%, and the mixed gas consists of hydrogen and inert gas; the metal catalyst is selected from at least one of palladium on carbon, palladium hydroxide, platinum oxide, palladium on alumina, platinum on activated carbon, and raney nickel.
2. The method according to claim 1, wherein the mixed gas contains 50 to 75% of hydrogen.
3. The method according to claim 1, wherein the metal catalyst is selected from palladium on carbon and palladium hydroxide.
4. The process according to claim 1, wherein the compound of formula II is
Wherein R is2Is an amino protecting group.
5. The method according to claim 4, wherein R is2Is benzyl.
6. The process according to any one of claims 1 to 3, wherein the compound of formula II is
7. The process according to any one of claims 1 to 5, wherein the salt of the compound of formula II is tosylate, methoxybenzenesulfonate or nitrobenzenesulfonate.
8. The method according to claim 7, wherein the salt of the compound of formula II is a tosylate salt.
9. The preparation method according to claim 1, wherein the compound of formula II is obtained by ring-opening reaction of a compound of formula III with a compound of formula IV,
wherein R is1And R2As claimed in claim 1.
10. The process according to claim 9, wherein the solvent used in the ring-opening reaction is selected from the group consisting of dimethyl sulfoxide, N-dimethylformamide, acetonitrile, N-methylpyrrolidone and C3-C6At least one ketone solvent of (1).
11. The method according to claim 10, wherein the solvent used in the ring-opening reaction is dimethyl sulfoxide or N, N-dimethylformamide.
12. The process according to any one of claims 1 to 5, wherein the solvent used in the catalytic hydrogenation is at least one selected from the group consisting of ethyl acetate, methanol, ethanol, propanol, butanol, pentanol, N-dimethylformamide, toluene, benzene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, acetic acid, trifluoroacetic acid, water and dichloromethane.
13. The method according to claim 12, wherein the solvent used in the catalytic hydrogenation is at least one selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, acetic acid, and trifluoroacetic acid.
14. A process for the preparation of a pharmaceutically acceptable salt of indacaterol comprising the steps of obtaining indacaterol by the process of any one of claims 1 to 13 and then forming the salt with an acid selected from benzoic acid, maleic acid, succinic acid, fumaric acid, tartaric acid.
15. The method according to claim 14, wherein the acid is maleic acid.
16. The method according to claim 14 or 15, wherein the solvent used in the salt forming step is selected from at least one of methanol, ethanol, propanol, butanol, pentanol, ethyl acetate, and dichloromethane.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611042383 | 2016-11-24 | ||
| CN2016110423834 | 2016-11-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108101841A CN108101841A (en) | 2018-06-01 |
| CN108101841B true CN108101841B (en) | 2021-04-06 |
Family
ID=62206550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711181431.2A Active CN108101841B (en) | 2016-11-24 | 2017-11-23 | Method for preparing indacaterol or salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108101841B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113912536A (en) * | 2020-07-07 | 2022-01-11 | 四川海思科制药有限公司 | Indacaterol hydrate, and preparation method and application thereof |
| CN114591236A (en) * | 2020-12-02 | 2022-06-07 | 四川海思科制药有限公司 | A kind of improved preparation method of indacaterol |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1156451C (en) * | 1999-06-04 | 2004-07-07 | 诺瓦提斯公司 | Betz 2-adrenoceptor agonists |
| CN1753874A (en) * | 2003-02-28 | 2006-03-29 | 诺瓦提斯公司 | Process for preparing 5-'(r)-2-(5,6-diethyl-indian-2-ylamin o)-1-hydroxy-ethyl-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist |
| CN102666440A (en) * | 2009-11-26 | 2012-09-12 | 桑多斯股份公司 | Reduction of organic compounds with low amounts of hydrogen |
| WO2014008639A1 (en) * | 2012-07-11 | 2014-01-16 | 上海威智医药科技有限公司 | Method for preparing indacaterol |
| WO2014044288A1 (en) * | 2012-09-21 | 2014-03-27 | Crystal Pharma Sa | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
-
2017
- 2017-11-23 CN CN201711181431.2A patent/CN108101841B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1156451C (en) * | 1999-06-04 | 2004-07-07 | 诺瓦提斯公司 | Betz 2-adrenoceptor agonists |
| CN1753874A (en) * | 2003-02-28 | 2006-03-29 | 诺瓦提斯公司 | Process for preparing 5-'(r)-2-(5,6-diethyl-indian-2-ylamin o)-1-hydroxy-ethyl-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist |
| CN102666440A (en) * | 2009-11-26 | 2012-09-12 | 桑多斯股份公司 | Reduction of organic compounds with low amounts of hydrogen |
| WO2014008639A1 (en) * | 2012-07-11 | 2014-01-16 | 上海威智医药科技有限公司 | Method for preparing indacaterol |
| WO2014044288A1 (en) * | 2012-09-21 | 2014-03-27 | Crystal Pharma Sa | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| An investigation into the structure–activity relationships associated with the systematic modification of the β2-adrenoceptor agonist indacaterol;David Beattie et al.;《Bioorganic & Medicinal Chemistry Letters》;20120804;第22卷(第19期);第6280-6285页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108101841A (en) | 2018-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2300431B1 (en) | Process for the manufacture of an intermediate in the synthesis of dabigatran | |
| US10927095B2 (en) | Processes for the preparation of Niraparib and intermediates thereof | |
| CN108101841B (en) | Method for preparing indacaterol or salt thereof | |
| CN103183673B (en) | The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane | |
| CN109748902B (en) | Preparation method of erlotinib hydrochloride | |
| CN107056681B (en) | A kind of support method replaces the preparation method of cloth intermediate | |
| CN112300073B (en) | Preparation method of isoquinoline derivative | |
| EP3081554B1 (en) | Method for preparing silodosin and intermediate thereof | |
| CN107118211A (en) | The preparation method of the western croak of Leo | |
| CN107674026B (en) | Preparation method of ruxolitinib intermediate (3R) -3- (4-bromo-1H-pyrazol-1-yl) -cyclopentyl propionitrile | |
| CN110234626B (en) | Process for producing optically active pyrrolidine compound | |
| CN113354599B (en) | Preparation method of nintedanib key intermediate | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN112679363B (en) | Method for preparing pentazocine intermediate | |
| CN113788829A (en) | Preparation method of genotoxic impurity of tartaric acid varenicline N-nitrosamine | |
| CN107151244A (en) | The recovery preparation method of racemization pyrrole quinoline amine | |
| CN111302962A (en) | Rapid method for reducing nitro in aliphatic nitro compound into amino | |
| CN110627768A (en) | Preparation method of moxifloxacin degradation impurity J | |
| CN115490626B (en) | Key chiral compound of PF-07321332 and preparation method thereof | |
| CN113999239B (en) | Method for synthesizing diaza-bridge compound | |
| CN114539133B (en) | Method for preparing prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine | |
| CN116444380B (en) | Method for realizing amino derivative alkylation by utilizing micro-flow field technology | |
| CN113816917B (en) | Preparation method of wibeled intermediate | |
| CN110734424B (en) | Preparation method of vonoprazan fumarate | |
| CN108530375B (en) | Intermediate of 4-oxa-7-azaspiro[2.5]octane or its salt and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |