CN103254156A - Preparation method of afatinib intermediate - Google Patents
Preparation method of afatinib intermediate Download PDFInfo
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- CN103254156A CN103254156A CN2013101736910A CN201310173691A CN103254156A CN 103254156 A CN103254156 A CN 103254156A CN 2013101736910 A CN2013101736910 A CN 2013101736910A CN 201310173691 A CN201310173691 A CN 201310173691A CN 103254156 A CN103254156 A CN 103254156A
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- tetrahydrofuran
- thf
- buddhist nun
- oxygen base
- amino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 title abstract description 4
- 229960001686 afatinib Drugs 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 27
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000006266 etherification reaction Methods 0.000 claims abstract description 11
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 60
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
- 239000001301 oxygen Substances 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 239000000543 intermediate Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 230000009471 action Effects 0.000 claims description 10
- 229940059260 amidate Drugs 0.000 claims description 10
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 10
- 238000006396 nitration reaction Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 5
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 claims description 2
- 229960001826 dimethylphthalate Drugs 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YZCLFYPXHSRNHI-UHFFFAOYSA-N tributyl(methylidene)-$l^{5}-phosphane Chemical compound CCCCP(=C)(CCCC)CCCC YZCLFYPXHSRNHI-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 230000009435 amidation Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- -1 3-chloro-4-fluorophenyl Chemical group 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100170601 Drosophila melanogaster Tet gene Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 239000005785 Fluquinconazole Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- FRJZRJQWLFVEDT-UHFFFAOYSA-K O.[Cl-].[Cl-].[Cl-].[Fe+3].NN Chemical compound O.[Cl-].[Cl-].[Cl-].[Fe+3].NN FRJZRJQWLFVEDT-UHFFFAOYSA-K 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of an afatinib intermediate. The preparation method comprises the following steps of: sequentially carrying out nitrification, etherification, reduction, amidation, nitrification and reduction on 4-cyanol phenol serving as the starting raw material to prepare 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino-5-[(S)-tetrahydrofuran-3-yl]oxy]phenylamine (I). The preparation method has the advantages that the process is stable, raw materials are easily available, cost is low and all reactions are classic reactions; therefore, the preparation method meets the requirement of industrial amplification.
Description
But other two applications for a patent for invention that patent REFERENCE TO RELATED people of the present invention submits on the same day, its title are respectively " a kind of Ah method is for Buddhist nun's preparation method " and " Ah method is for Buddhist nun's preparation method ".
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of Ah method is for Buddhist nun's intermediates preparation.
Background technology
Ah method is for Buddhist nun (Afatinib, chemistry 4-[(3-chloro-4-fluorophenyl by name) amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] amino }-7-[(S)-(tetrahydrofuran (THF)-3-yl) oxygen base] quinazoline) be first for the lung cancer therapy medicine after the epidermal growth factor receptor inhibitor treatment failure by the Boehringer Ingelheim company research and development of Germany.Can be used for the treatment of advanced lung cancer, mammary cancer and intestinal cancer clinically.This medicine on February 15th, 2008 by FDA (Food and Drug Adminstration) (FDA) examine passage fast, commodity are called Tovok.
The former world patent that grinds of Boehringer Ingelheim company has been reported the preparation method of Ah method for the Buddhist nun for WO0250043A1 number and WO03094921A2 number: with parent nucleus 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-fluquinconazole quinoline (VII) is raw material, pass through the conversion reaction of functional groups such as replacement, reduction, amidation and amination successively, the Ah method that obtains is for the Buddhist nun.
In order to overcome that existing Ah method is on the high side for the step that exists among the Buddhist nun preparation method, yield is on the low side and defective such as purification difficult, two other Chinese invention patent application that applicant and patent application of the present invention are submitted has on the same day disclosed new Ah method respectively for Buddhist nun's preparation method, its patent name is respectively " a kind of Ah method for Buddhist nun preparation method " and " Ah method is for Buddhist nun's preparation method ", can with the mutual reference of present patent application.These two applications for a patent for invention are all with intermediate 2-itrile group-4-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (I) is raw material, makes Ah method for the Buddhist nun by condensation and the cyclisation reaction of " treating different things alike ".Yet, the preparation method who discloses this intermediate (I) is not arranged, so be necessary to provide a kind of new preparation method to this intermediate (I) in the prior art.
Summary of the invention
The object of the present invention is to provide a kind of Ah method for Buddhist nun's intermediate 2-itrile group-4-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] preparation method of aniline, this preparation method's process stabilizing, raw material be easy to get, with low cost, institute responds and is classical reaction, is fit to industrialization and amplifies requirement.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of Ah method is for Buddhist nun's intermediate 2-itrile group-4-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] preparation method of aniline (I)
It is characterized in that described preparation method comprises the steps: that with the para hydroxybenzene nitrile be starting raw material, make 3-nitro-4-4-hydroxy-benzonitrile (II) by nitration reaction one, etherification reaction makes the oxygen base of 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (III), reduction reaction one makes the oxygen base of 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (IV), amidate action makes 3-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (V), nitration reaction two makes 2-nitro-5-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (VI) and reduction reaction two prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (I).
The raw material of described etherification reaction is 3-nitro-4-4-hydroxy-benzonitrile (II) and (S)-3-hydroxyl tetrahydrofuran, and its molar ratio is 1: 1-3, preferred 1: 1.5-2.5.
The promotor one of described etherification reaction is diethylazodicarboxylate (DEAD), diisopropyl azo-2-carboxylic acid (DIAD), azo-2-carboxylic acid's dipropyl (DPAD), azodicarboxy dimethyl phthalate (DMAD), azo-2-carboxylic acid's two p-chlorobenzyls (DCAD), N, N, N ', N '-tetramethyl-azodicarboxy acid amides (TMAD), N, N, N ', N '-tetra isopropyl azodicarboxy acid amides (TIPA) or azo two formyls, two piperidines (ADDP), preferred diethylazodicarboxylate (DEAD) or diisopropyl azo-2-carboxylic acid (DIAD).
The promotor two of described etherification reaction is triphenylphosphine (TPP), tributylphosphine (TBP), trimethyl-phosphine (TMA) or cyano group methylene tri butyl phosphorane (CMBP), triphenylphosphine (TPP) or tributylphosphine (TBP).
The solvent of described etherification reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, dioxane, methylene dichloride, chloroform, 1,2-ethylene dichloride, methyl-sulphoxide, acetonitrile, N, dinethylformamide, acetone or tetrahydrofuran (THF), preferred methylene dichloride or tetrahydrofuran (THF).
The raw material of described amidate action is the oxygen base of 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (IV) and 4-(N, N-dimethylamino)-2-alkene-butyryl chloride, its molar ratio is 1: 1-2, preferred 1: 1.1-1.3.
The acid binding agent of described amidate action is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood, preferred triethylamine or salt of wormwood.
The solvent of described amidate action is methylene dichloride, trichloromethane, toluene, acetonitrile or methyl-sulphoxide, preferred methylene dichloride.
The temperature of described amidate action is 0-60 ℃, preferred 20-25 ℃.
Than prior art, Ah method involved in the present invention is for Buddhist nun's intermediate 2-itrile group-4-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] preparation method of aniline, its major advantage be process stabilizing, raw material be easy to get, with low cost, institute responds and is classical reaction, is fit to industrialization and amplifies requirement.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive explanation.
Wherein, nitration reaction one, reduction reaction one, nitration reaction two and reduction reaction two are known classical reaction.Particularly, nitration reaction can be rolled up the 5393rd page of the 40th phase referring to " chemistry world " 2003 25 the 237th page of the 4th phases of volume or " Tetrahedron Letters " in 2012 53.Reduction reaction can adopt palladium hydrogenated carbon system, iron powder acetate system, hydrazine hydrate iron trichloride system or V-Brite B (vat powder) system.
Side chain (S)-3-hydroxyl tetrahydrofuran and 4-(N, N-dimethylamino)-2-alkene-butyryl chloride can be referring to world patent WO0250043A1 number and the WO03094921A2 number description to the similar compound preparation method.
Embodiment one:
Under the room temperature, (3mL, 15mmol) with tetrahydrofuran (THF) 5mL, (4.0g, tetrahydrofuran (THF) 25mL solution 15mmol) kept room temperature reaction 2 hours to drip triphenylphosphine under the room temperature to add the diisopropyl azo-2-carboxylic acid in the 100mL there-necked flask.Under nitrogen protection, with (S)-3-hydroxyl tetrahydrofuran (0.3g, tetrahydrofuran (THF) 5mL solution 3.4mmol) dropwise joins in the above-mentioned reaction system; drip complete after; (0.5g, 3.0mmol), stirring at room was reacted 4 hours to add 3-nitro-4-4-hydroxy-benzonitrile (II).(0.23g, tetrahydrofuran (THF) 5mL solution 2.6mmol) continued room temperature reaction 2 hours, and the TLC monitoring reaction finishes to drip (S)-3-hydroxyl tetrahydrofuran.Vacuum distillation recovered solvent, resistates is transferred pH=5-6 with dilute hydrochloric acid, uses ethyl acetate extraction, and organic phase is transferred pH=10-11 with saturated sodium carbonate.Tell water, vacuum freezedrying gets the oxygen base of off-white color solid 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (III) 5.9g, yield is 83.8%.
Embodiment two:
In the 100mL there-necked flask, add the oxygen base of 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] and cyanophenyl (IV) (0.51g, 2.5mmol), (0.25g 2.5mmol) and methylene dichloride 20mL, is warming up to 40-45 ℃ to triethylamine, is stirred to system dissolving homogeneous.Be down to below 10 ℃, (0.42g, methylene dichloride 10mL solution 2.8mmol) drip off the back room temperature and continue reaction 6 hours, and the TLC detection reaction finishes slowly to drip 4-(N, N-dimethylamino)-2-alkene-butyryl chloride.Reaction solution is used 10% sodium hydrogen carbonate solution and water washing, anhydrous sodium sulfate drying respectively.Decompression and solvent recovery, the residuum re-crystallizing in ethyl acetate obtains white solid 3-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (V) 0.72g, yield 91.4%.
Embodiment three:
In the hydrogenation still, add 2-nitro-5-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (VI) (3.6g, 10mmol), (0.36g is 10%w/w) with ethanol 50mL for 5% palladium charcoal.Room temperature keeps 3-4 kilogram pressure, reacts about 12 hours.Suction filtration reclaims palladium carbon catalyst.Decompression recycling ethanol, the resistates re-crystallizing in ethyl acetate gets white solid 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (I) 3.1g, yield is 94.0%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (9)
1. an Ah method is for Buddhist nun's intermediate 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] preparation method of aniline (I),
It is characterized in that described preparation method comprises the steps: that with the para hydroxybenzene nitrile be starting raw material, make 3-nitro-4-4-hydroxy-benzonitrile (II) by nitration reaction one, etherification reaction makes the oxygen base of 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (III), reduction reaction one makes the oxygen base of 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (IV), amidate action makes 3-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (V), nitration reaction two makes 2-nitro-5-[4-(N, the N-dimethylamino)-and 1-oxo-2-butylene-1-yl] the oxygen base of amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (VI) and reduction reaction two prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-yl] the oxygen base of amino-5-[(S)-(tetrahydrofuran (THF)-3-yl)] aniline (I).
According to the described Ah method of claim 1 for Buddhist nun's intermediates preparation, it is characterized in that: the raw material of described etherification reaction is 3-nitro-4-4-hydroxy-benzonitrile (II) and (S)-3-hydroxyl tetrahydrofuran, and its molar ratio is 1: 1-3.
3. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 2, it is characterized in that: the promotor one of described etherification reaction is diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, azo-2-carboxylic acid's dipropyl, azodicarboxy dimethyl phthalate, azo-2-carboxylic acid's two p-chlorobenzyls, N, N, N ', N '-tetramethyl-azodicarboxy acid amides, N, N, N ', N '-tetra isopropyl azodicarboxy acid amides or azo two formyls two piperidines.
4. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 2, it is characterized in that: the promotor two of described etherification reaction reaction is triphenylphosphine, tributylphosphine, trimethyl-phosphine or cyano group methylene tri butyl phosphorane.
5. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 2, it is characterized in that: the solvent of described etherification reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, dioxane, methylene dichloride, chloroform, 1,2-ethylene dichloride, methyl-sulphoxide, acetonitrile, N, dinethylformamide, acetone or tetrahydrofuran (THF).
6. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 1, it is characterized in that: the raw material of described amidate action is the oxygen base of 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-yl)] cyanophenyl (IV) and 4-(N, the N-dimethylamino)-and 2-alkene-butyryl chloride, its molar ratio is 1: 1-2.
7. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 6, it is characterized in that: the acid binding agent of described amidate action is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood.
8. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 6, it is characterized in that: the solvent of described amidate action is methylene dichloride, trichloromethane, toluene, acetonitrile or methyl-sulphoxide.
9. replace Buddhist nun's intermediates preparation according to the described Ah method of claim 6, it is characterized in that: the temperature of described amidate action is 0-60oC.
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| CN104478863A (en) * | 2014-12-23 | 2015-04-01 | 康伯莱（天津）药物研发有限责任公司 | Preparation method of Afatinib |
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