CN103254156B - Ah method is for the preparation method of Buddhist nun's intermediate - Google Patents
Ah method is for the preparation method of Buddhist nun's intermediate Download PDFInfo
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- CN103254156B CN103254156B CN201310173691.0A CN201310173691A CN103254156B CN 103254156 B CN103254156 B CN 103254156B CN 201310173691 A CN201310173691 A CN 201310173691A CN 103254156 B CN103254156 B CN 103254156B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 76
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 61
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000001301 oxygen Substances 0.000 claims abstract description 24
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 12
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 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
- 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 group CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006266 etherification reaction Methods 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-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
- 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
- OZMLUMPWPFZWTP-UHFFFAOYSA-N 2-(tributyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CCCCP(CCCC)(CCCC)=CC#N OZMLUMPWPFZWTP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 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
- 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
- 229940043232 butyl acetate Drugs 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
- 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
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 230000000087 stabilizing effect Effects 0.000 abstract description 3
- 230000009435 amidation Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 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
- 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 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 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
- 238000005576 amination reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 230000007547 defect Effects 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
- 238000005516 engineering process 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
- 238000012544 monitoring process Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012074 organic phase Substances 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling 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
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
Present invention is disclosed the preparation method of a kind of Ah method for Buddhist nun's intermediate, comprise the steps: with para hydroxybenzene nitrile as starting raw material, successively by the step such as nitrated, etherificate, reduction, amidation, nitrated and reduction, prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I).This preparation method's process stabilizing, raw material are easy to get, with low cost, institute responds and is classical reaction, is applicable to industrialization and amplifies requirement.
Description
Patent of the present invention can the REFERENCE TO RELATED people other two pieces application for a patent for invention of submitting on the same day, and its title is respectively " a kind of Ah method is for the preparation method of Buddhist nun " and " Ah method is for the preparation method of Buddhist nun ".
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of Ah method is for the preparation method of Buddhist nun's intermediate.
Background technology
Ah method is for Buddhist nun (Afatinib, chemistry 4-by name [(3-chloro-4-fluorophenyl) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] is amino }-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline) be by the Boehringer Ingelheim company of Germany research and develop first for the lung cancer therapy medicine after epidermal growth factor receptor inhibitor Endodontic failure.Can be used for the treatment of advanced lung cancer, mammary cancer and intestinal cancer clinically.The quick examination & approval passage of this medicine on February 15th, 2008 by FDA (Food and Drug Adminstration) (FDA), commodity are called Tovok.
No. WO0250043A1st, the former world patent ground of Boehringer Ingelheim company and No. WO03094921A2 report the preparation method of Ah method for Buddhist nun: with parent nucleus 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-fluquinconazole quinoline (VII) for raw material, successively through the conversion reaction of the functional groups such as replacement, reduction, amidation and amination, the Ah method that obtains is for Buddhist nun.
In order to overcome that existing Ah method is on the high side for the step existed in Buddhist nun preparation method, yield is on the low side and the defect such as purification difficult, two other Chinese invention patent application that applicant and patent application of the present invention are submitted on the same day discloses the preparation method of new Ah method for Buddhist nun respectively, its patent name is respectively " a kind of Ah method is for the preparation method of Buddhist nun " and " Ah method is for the preparation method of Buddhist nun ", can reference mutual to present patent application.These two applications for a patent for invention are all with intermediate 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I) is raw material, " treats different things alike " the obtained Ah's method of reaction for Buddhist nun by condensation and cyclisation.But, there is not the preparation method disclosing this intermediate (I) in prior art, so be necessary to provide a kind of new preparation method to this intermediate (I).
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, N-dimethylamino)-1-oxo-2-butylene-1-base] preparation method of amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline, this preparation method's process stabilizing, raw material are easy to get, with low cost, institute responds and is classical reaction, is applicable 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, N-dimethylamino)-1-oxo-2-butylene-1-base] preparation method of amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I)
It is characterized in that described preparation method comprises the steps: with para hydroxybenzene nitrile as starting raw material, 3-nitro-4-4-hydroxy-benzonitrile (II) is obtained by nitration reaction one, etherification reaction obtains 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (III), reduction reaction one obtains 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (IV), amidate action obtains 3-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (V), nitration reaction two obtains 2-nitro-5-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (VI) and reduction reaction two prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] 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, preferably 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 two p-chlorobenzyl (DCAD), N, N, N ', N '-tetramethyl-azodicarboxy acid amides (TMAD), N, N, N ', N '-tetra isopropyl azodicarboxy acid amides (TIPA) or azodicarbonyldipiperidine (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 cyanomethylene tributyl 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 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (IV) and 4-(N, N-dimethylamino)-2-alkene-butyryl chloride, its molar ratio is 1: 1-2, preferably 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, sodium carbonate, 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 DEG C, preferred 20-25 DEG C.
Compared to prior art, Ah method involved in the present invention is for Buddhist nun's intermediate 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] preparation method of amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline, its major advantage is process stabilizing, raw material is easy to get, with low cost, institute responds and is classical reaction, is applicable to industrialization and amplifies requirement.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described.
Wherein, nitration reaction one, reduction reaction one, nitration reaction two and reduction reaction two are known classics reaction.Particularly, nitration reaction can see " chemistry world " 25 volumes the 4th phase in 2003 the 237th page or " Tetrahedron Letters " 53 volumes the 40th phase in 2012 the 5393rd page.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 see No. WO0250043A1st, world patent and No. WO03094921A2 descriptions to similar compound preparation method.
Embodiment one:
Under room temperature, in 100mL there-necked flask, add diisopropyl azo-2-carboxylic acid (3mL, 15mmol) and tetrahydrofuran (THF) 5mL, under room temperature, drip the tetrahydrofuran (THF) 25mL solution of triphenylphosphine (4.0g, 15mmol), keep room temperature reaction 2 hours.Under nitrogen protection; by (S)-3-hydroxyl tetrahydrofuran (0.3g; tetrahydrofuran (THF) 5mL dropwise 3.4mmol) joins in above-mentioned reaction system; drip standby after; add 3-nitro-4-4-hydroxy-benzonitrile (II) (0.5g; 3.0mmol), stirring at room temperature reacts 4 hours.Drip the tetrahydrofuran (THF) 5mL solution of (S)-3-hydroxyl tetrahydrofuran (0.23g, 2.6mmol), continue room temperature reaction 2 hours, TLC monitoring reaction terminates.Vacuum distillation recovered solvent, resistates dilute hydrochloric acid adjusts pH=5-6, is extracted with ethyl acetate, and organic phase saturated sodium carbonate adjusts pH=10-11.Separate aqueous phase, vacuum freezedrying, obtain off-white color solid 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (III) 5.9g, yield is 83.8%.
Embodiment two:
3-amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (IV) (0.51g is added in 100mL there-necked flask, 2.5mmol), triethylamine (0.25g, 2.5mmol) with methylene dichloride 20mL, be warming up to 40-45 DEG C, the system that is stirred to is dissolved homogeneous.Be down to less than 10 DEG C, slowly drip the methylene dichloride 10mL solution of 4-(N, N-dimethylamino)-2-alkene-butyryl chloride (0.42g, 2.8mmol), drip off rear room temperature and continue reaction 6 hours, TLC detection reaction terminates.Reaction solution uses 10% sodium hydrogen carbonate solution and water washing respectively, anhydrous sodium sulfate drying.Decompression and solvent recovery, residuum re-crystallizing in ethyl acetate, obtain white solid 3-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (V) 0.72g, yield 91.4%.
Embodiment three:
2-nitro-5-[4-(N is added in hydrogenation reaction cauldron, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (VI) (3.6g, 10mmol), 5% palladium charcoal (0.36g, 10%w/w) and ethanol 50mL.Room temperature keeps 3-4 kilogram of pressure, reacts about 12 hours.Suction filtration, Recover palladium Pd/carbon catalyst.Decompression recycling ethanol, residue with ethyl acetate recrystallization, obtain white solid 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I) 3.1g, yield is 94.0%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (7)
1. an Ah method is for Buddhist nun's intermediate 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] preparation method of amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I)
It is characterized in that described preparation method comprises the steps: with para hydroxybenzene nitrile as starting raw material, 3-nitro-4-4-hydroxy-benzonitrile (II) is obtained by nitration reaction one, diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, azo-2-carboxylic acid's dipropyl, azodicarboxy dimethyl phthalate, azo-2-carboxylic acid two p-chlorobenzyl, N, N, N', N'-tetramethyl-azodicarboxy acid amides, N, N, N', N'-tetra isopropyl azodicarboxy acid amides or azodicarbonyldipiperidine and triphenylphosphine, tributylphosphine, there is etherification reaction under trimethyl-phosphine or cyanomethylene tributyl phosphorane existent condition and obtain 3-nitro-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (III), reduction reaction one obtains 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (IV), under acid binding agent existent condition, there is amidate action obtain 3-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (V), nitration reaction two obtains 2-nitro-5-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (VI) and reduction reaction two prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I).
2. Ah method, for the preparation method of Buddhist nun's intermediate, 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 according to claim 1.
3. Ah method replaces the preparation method of Buddhist nun's intermediate according to 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, DMF, acetone or tetrahydrofuran (THF).
4. Ah method replaces the preparation method of Buddhist nun's intermediate according to claim 1, it is characterized in that: the raw material of described amidate action is 3-amino-4-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] cyanophenyl (IV) and 4-(N, N-dimethylamino)-2-alkene-butyryl chloride, its molar ratio is 1:1-2.
5. Ah method, for the preparation method of Buddhist nun's intermediate, is characterized in that: the acid binding agent of described amidate action is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, potassium hydroxide, sodium carbonate, sodium bicarbonate or salt of wormwood according to claim 4.
6. Ah method, for the preparation method of Buddhist nun's intermediate, is characterized in that: the solvent of described amidate action is methylene dichloride, trichloromethane, toluene, acetonitrile or methyl-sulphoxide according to claim 4.
7. Ah method, for the preparation method of Buddhist nun's intermediate, is characterized in that: the temperature of described amidate action is 0-60 DEG C according to claim 4.
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| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
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