CN112125888A - Preparation method of 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine - Google Patents
Preparation method of 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- BISOXOHVBZOOFL-UHFFFAOYSA-N 3-(1-methylpyrazol-4-yl)quinoxalin-6-amine Chemical compound C1=NN(C)C=C1C1=CN=C(C=CC(N)=C2)C2=N1 BISOXOHVBZOOFL-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000006467 substitution reaction Methods 0.000 claims abstract description 11
- LXQOQPGNCGEELI-UHFFFAOYSA-N 2,4-dinitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O LXQOQPGNCGEELI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229950004444 erdafitinib Drugs 0.000 claims abstract description 5
- -1 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid Chemical compound 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- PLMCCOPFYJURPS-UHFFFAOYSA-N 4-bromo-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CBr PLMCCOPFYJURPS-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- 238000006482 condensation reaction Methods 0.000 claims description 10
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 7
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 6
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 5
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 claims description 3
- 229940118019 malondialdehyde Drugs 0.000 claims description 3
- YNUKVBWZLAROPU-UHFFFAOYSA-N 7-bromo-2-(1-methylpyrazol-4-yl)quinoxaline Chemical compound C1=NN(C)C=C1C1=CN=C(C=CC(Br)=C2)C2=N1 YNUKVBWZLAROPU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 8
- 238000006243 chemical reaction Methods 0.000 abstract description 22
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000006476 reductive cyclization reaction Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- BHFGEPMLMSSSSI-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-3-(1-methylpyrazol-4-yl)quinoxalin-6-amine Chemical compound COC1=CC(OC)=CC(NC=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 BHFGEPMLMSSSSI-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229940124649 Balversa Drugs 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- KRWRFIMBWRVMKE-UHFFFAOYSA-N 1-bromo-3,5-dimethoxybenzene Chemical compound COC1=CC(Br)=CC(OC)=C1 KRWRFIMBWRVMKE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VAQYGOTYKYMSRX-UHFFFAOYSA-N 1h-pyrazole;quinoxaline Chemical compound C=1C=NNC=1.N1=CC=NC2=CC=CC=C21 VAQYGOTYKYMSRX-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical group CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SFRKVRBYLCHDBI-UHFFFAOYSA-N n-(2-chloroethyl)propan-2-amine;hydrochloride Chemical compound Cl.CC(C)NCCCl SFRKVRBYLCHDBI-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CQKAPARXKPTKBK-UHFFFAOYSA-N tert-butylazanium;bromide Chemical compound Br.CC(C)(C)N CQKAPARXKPTKBK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of erdamitinib (Erdafitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine, which takes 2, 4-dinitroaniline as a starting raw material to prepare a target intermediate through basic unit reactions such as substitution, reductive cyclization, oxidation, condensation and the like in sequence. The preparation process has the advantages of easily available raw materials, rapidness, convenience, economy, environmental friendliness and suitability for large-scale production, and provides a new preparation way for industrialization of erdastinib.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of an erdastinib intermediate which can be used for treating advanced or metastatic bladder cancer.
Background
Erdamitinib (Erdafitinib) is an FGFR inhibitor discovered by Astex pharmaceuticals and developed by poplar pharmaceuticals under the grand flag of the american pharmaceutical university. The drug has once been qualified by us FDA for breakthrough therapy approval and priority. Erdafitinib obtained us FDA approval for marketing in 2019 in month 4 under the trade name Balversa. Balversa is the first FDA approved FGFR kinase inhibitor in the united states as an oral pan FGFR inhibitor that is useful in the treatment of locally advanced or metastatic bladder cancer in adult patients. Because the medicine is not yet on the market formally in China and does not have a standard Chinese translation name, the applicant translates the medicine into Ervatinib.
The chemical name of ervatinib is: n is a radical of1- (3, 5-dimethoxyphenyl) -N2- (1-methylethyl) -N1- [3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinyl]1, 2-ethyldiamine.
International patents WO2011135376, WO2012073017 and WO2019109069 report synthetic routes and preparation methods of erdastinib or analogs thereof. The basic synthesis thought is that substituted quinoxaline mother nucleus is used as a raw material, on one hand, halogen substitution is formed on quinoxaline, and then quinoxaline pyrazole intermediate is formed by carrying out Suzuki carbon-carbon coupling reaction on different halogen functional groups and a borate derivative of a 1-methylpyrazole ring; on the other hand, another halogen functional group on the quinoxaline and the side chain amino group are subjected to substitution reaction to form another amino group side chain. Of course, the formation of the side chain of the amino group can also be completed by converting the nitro group on the quinoxaline ring into the amino group and then performing an amino substitution reaction with the corresponding halohydrocarbon.
The synthesis methods of ervatinib and derivatives thereof described in the prior documents are examined, although the preparation methods of quinoxaline mother nucleus and amino side chain amine are different, the linking sequence and time of the quinoxaline mother nucleus, pyrazole and amino side chain are different, and the selection of the reaction of a basic unit in the preparation process is different, the quinoxaline and pyrazole side chain are prepared by adopting the steps of firstly halogenating and then carrying out carbon-carbon coupling reaction with the borate of pyrazole; the synthetic route is shown as follows:
it can be seen that one of the key technologies in the synthesis of erdamatinib is to solve the synthesis of two intermediates a or B that overcome positional isomerism that may occur when linking pyrazoles.
How to efficiently and quickly prepare the core intermediate 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (A) or 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (B) has very important practical significance for preparing erdintinib. Therefore, the research adopts a new synthesis technology, overcomes position isomerism of amino and timely reduction and conversion of nitro, and conveniently and quickly prepares a target intermediate. The preparation technology provides a new valuable way for the industrial production of the erdasatinib bulk drug.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a preparation method of an improved Erdasatinib (Erdacitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) according to a synthesis concept of green chemistry, wherein the preparation method is novel in design and simple in steps, is beneficial to quality improvement and industrial production of the medicine, and can promote economic and technical development of the bulk drug.
In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a preparation method of an erdaminib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I),
the preparation method comprises the following steps: the preparation method comprises the following steps: 2, 4-dinitroaniline (II), 2, 4-dinitroaniline and 4-bromo-3-oxo-butyric acid are subjected to substitution reaction to prepare 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid (III), the 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid (III) and sodium hydrosulfite are subjected to reduction cyclization reaction to prepare 7-amino-2-quinoxaline acetic acid (IV), the 7-amino-2-quinoxaline acetic acid (IV) and phosphorus oxychloride and sodium perchlorate are subjected to oxidation reaction in N, N-dimethylformamide to prepare 2- (7-amino-quinoxaline-2-yl) malonaldehyde (V), and the 2- (7-amino-quinoxaline-2-yl) malonaldehyde (V) and sodium perchlorate are subjected to oxidation reaction in N, N-dimethylformamide to prepare 2- (7-amino-quinoxaline-2-yl) malonaldehyde (V) N-methyl hydrazine is subjected to condensation reaction to prepare the erdamitinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I), and the synthetic route is shown as follows:
in addition, the invention also provides the following auxiliary technical scheme:
the feed ratio of the condensation reaction is 2, 4-dinitroaniline (II) (1 equivalent) and 4-bromo-3-oxo-butyric acid (0.5 to 1.5 equivalents), preferably 2, 4-dinitroaniline (II) (1 equivalent) and 4-bromo-3-oxo-butyric acid (1 equivalent).
The solvent for the substitution reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water, preferably water.
The temperature of the substitution reaction is 50-150 ℃, and preferably 100-110 ℃.
The feeding ratio of the reduction cyclization reaction is that the feeding ratio of the reduction cyclization reaction is 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid (1 equivalent) and sodium hydrosulfite (5-7 equivalents), and the feeding ratio of the reduction cyclization reaction is preferably 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid (1 equivalent) and sodium hydrosulfite (6 equivalents).
The solvent for the reductive cyclization reaction is methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane, N-dimethylformamide or water, preferably water.
The temperature of the reduction cyclization reaction is 0-100 ℃, wherein the temperature of the reduction reaction is preferably 45-55 ℃, and the temperature of the cyclization reaction is preferably 80-90 ℃.
The feeding ratio of the oxidation reaction is 7-amino-2-quinoxaline acetic acid (1 equivalent), phosphorus oxychloride (2-4 equivalents) and sodium perchlorate (3-5 equivalents), and the preferable materials are 7-amino-2-quinoxaline acetic acid (1 equivalent), phosphorus oxychloride (3 equivalents) and sodium perchlorate (4 equivalents)
The temperature of the oxidation reaction is 50-150 ℃, and preferably 90-100 ℃.
The feeding ratio of the condensation reaction is 2- (7-amino-quinoxaline-2-yl) malonaldehyde (1 equivalent) and N-methyl hydrazine (0.5-1.5 equivalent), preferably 2- (7-amino-quinoxaline-2-yl) malonaldehyde (1 equivalent) and N-methyl hydrazine (1 equivalent).
The solvent of the condensation reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water, preferably ethanol.
The condensation reaction temperature is 50-120 ℃, and preferably 80-85 ℃.
Using the target intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) prepared above, reference is made to WO2011135376A1, whereby idatinib can be conveniently prepared according to the following reaction scheme:
the preparation method of the erdaminib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxaline amine (I) uses 2, 4-dinitroaniline (II) as a starting material, and sequentially carries out substitution, reduction cyclization, oxidation, condensation and other reactions, so that the raw materials in the preparation process are easy to obtain, quick, convenient, economical and environment-friendly, and are suitable for large-scale industrial production.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Wherein, the preparation of the raw material 2, 4-dinitroaniline (II) is respectively referred to in the references Synthetic Communications,31(7), 1123-1127; 2001 "preparation of the same compound.
The first embodiment is as follows:
adding 2, 4-dinitroaniline (II) (9.2g, 50mmol), 4-bromo-3-oxo-butyric acid (9.1g, 50mmol) and 150mL of water into a reaction bottle, heating to 100-110 ℃, and carrying out reflux stirring reaction for 4-5 hours. Cooling to room temperature, extracting with ethyl acetate for three times, drying, and concentrating to obtain yellow oily 4- [ (2, 4-dinitro) phenyl group]Amino-3-oxo-butyric acid (III)14.2g, yield 86.2%, EI-MS M/z:284[ M + H%]+。
Example two:
adding 4- [ (2, 4-dinitro) phenyl group into a reaction bottle]Amino-3-oxo-butyric acid (III) (8.5g,30mmol), sodium dithionite (31.3g, 0.18mol) and water 300 mL. Stirring and reacting for 6-8 hours at 45-55 ℃. Filtering while the solution is hot, heating the filtrate to 80-90 ℃, and continuing to react for 8-10 hours. Cooling to room temperature, extracting with dichloromethane for three times, combining organic phases, washing with saturated sodium bicarbonate, saturated brine and water in sequence, drying, distilling under reduced pressure to recover solvent, and collecting the residue with ethyl acetateRecrystallizing in n-hexane (volume ratio 1:2) to obtain 4.3g of yellow oily 7-amino-2-quinoxaline acetic acid (IV), with yield of 70.6%, EI-MS M/z:204[ M + H ]]+。
Example three:
phosphorus oxychloride (9.2g,60mmol) and 30mL of N, N-dimethylformamide were added to a reaction flask at 0 deg.C, stirred for 1 hour and then warmed to room temperature. Adding 7-amino-2-quinoxaline acetic acid (IV) (4.1g,20mmol) into a reaction bottle, heating to 90-100 ℃, stirring for reaction for 4 hours, cooling to room temperature, and continuing the reaction for 12 hours. The reaction solution was poured into a solution containing sodium perchlorate (9.8g,80mmol) and 25g of ice-water, and a precipitate appeared, followed by filtration. Transferring the filter cake into a reaction bottle, adding 30mL of 1M sodium hydroxide solution, continuously heating to 90-100 ℃, and reacting for 2-4 hours. Cooling to room temperature, adjusting pH to neutrality with dilute hydrochloric acid, extracting with dichloromethane three times, combining organic phases, washing with saturated brine and water in sequence, and drying over anhydrous magnesium sulfate. Vacuum concentrating to dry to obtain yellow viscous substance 2- (7-amino-quinoxaline-2-yl) malonaldehyde (V)2.8g, yield 65.1%, EI-MS M/z 216[ M + H ]]+。
Example four:
adding 2- (7-amino-quinoxaline-2-yl) malondialdehyde (V) (2.8g,13mmol), N-methyldiamine (0.6g, 13mol) and 50mL of ethanol into a reaction bottle, and stirring and reacting for 4-6 hours at 80-85 ℃. Vacuum concentrating, recrystallizing the residue with ethyl acetate/n-hexane (volume ratio 1:2) to obtain 2.7g of 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) as light yellow solid with yield of 91.9%, EI-MS M/z:226[ M + H ])]+。
Example five:
under the protection of nitrogen, 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (I) (2.25g,10mmol), 3, 5-dimethoxy-1-bromobenzene (4.34g,20mmol), potassium tert-butoxide (0.11g,1mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (1.9g,3mmol) and ethylene glycol dimethyl ether 50mL are added into a reaction flask, stirred at room temperature for 30 minutes, palladium acetate (0.2g,1mmol) is added into the reaction flask, and the reaction is carried out for 1 hour under microwave heating to 135 ℃. Cooling to room temperature, adding potassium carbonate aqueous solution to quench reaction, extracting with ethyl acetate for three times, combining organic phases, washing with saturated brine and water in sequence, and drying with anhydrous sodium sulfateAnd (5) drying. Vacuum concentrating to dry to obtain off-white solid N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (VI)2.7g with the yield of 74.6 percent and EI-MS M/z of 362[ M + H ])]+。
Example six:
under the protection of nitrogen and at 0-5 ℃, N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine (VI) (1.8g and 5mmol), tert-butylammonium bromide (1.15g and 2.5mmol), potassium hydroxide (4.2g and 75mmol), tetrahydrofuran (100 mL) and water (5 mL) are added into a reaction bottle. The reaction was warmed to room temperature and stirred for 2 hours. N- (2-chloroethyl) -2-propylamine hydrochloride (1.6g,10mmol) was added thereto, and the reaction was stirred at 55 ℃ for 6 hours. Cooling to room temperature, adding dilute hydrochloric acid to adjust the pH value to be neutral, extracting with dichloromethane for three times, separating an organic phase, washing with saturated saline water and water in sequence, and drying with anhydrous magnesium sulfate. Vacuum concentrating to dryness and recrystallizing with isopropanol to obtain white solid Ervatinib (VII)1.9g with yield of 81.5%, EI-MS M/z:447[ M + H ]]+；1H NMR(DMSO-d6)8.96(s,1H),8.55(s,1H),8.21(s,1H),7.76(d,J＝9.4Hz,1H),7.27(m,1H),7.14(d,J＝2.4Hz,1H),6.47(d,J＝2.0Hz,2H),6.41(s,1H),3.90(m,5H),3.74(s,6H),3.35(brs,1H),2.80((t,J＝12.92,6.46Hz,2H),2.71(t,J＝12.2,6.10Hz,1H),0.96(d,J＝6.12Hz,6H)。
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A preparation method of Erdafitinib (Erdafitinib) intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine, wherein the chemical structural formula of the intermediate is as follows:
the preparation method is characterized by comprising the following steps: carrying out substitution reaction on 2, 4-dinitroaniline and 4-bromo-3-oxo-butyric acid to obtain 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid; the 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid and sodium hydrosulfite are subjected to reduction cyclization reaction to prepare 7-amino-2-quinoxaline acetic acid; the 7-amino-2-quinoxaline acetic acid, phosphorus oxychloride and sodium perchlorate are subjected to oxidation reaction in N, N-dimethylformamide to prepare 2- (7-amino-quinoxaline-2-yl) malondialdehyde; the 2- (7-amino-quinoxaline-2-yl) malondialdehyde and N-methyl hydrazine are subjected to condensation reaction to prepare the erdaminib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine.
2. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the condensation reaction is 2, 4-dinitroaniline (1 equivalent) and 4-bromo-3-oxo-butyric acid (0.5-1.5 equivalent).
3. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the solvent of the substitution reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water; the temperature of the substitution reaction is 50-150 ℃.
4. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the reduction cyclization reaction is 4- [ (2, 4-dinitro) phenyl ] amino-3-oxo-butyric acid (1 equivalent) and sodium hydrosulfite (5-7 equivalents).
5. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the solvent of the reduction cyclization reaction is methanol, ethanol, isopropanol, toluene, tetrahydrofuran, dioxane, N-dimethylformamide or water; the temperature of the reduction cyclization reaction is 0-100 ℃.
6. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the oxidation reaction is 7-amino-2-quinoxaline acetic acid (1 equivalent), phosphorus oxychloride (2-4 equivalents) and sodium perchlorate (3-5 equivalents).
7. The process for the preparation of ervatinib intermediate 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline according to claim 1, characterized in that: the temperature of the oxidation reaction is 50-150 ℃.
8. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the feeding ratio of the condensation reaction is 2- (7-amino-quinoxaline-2-yl) malonaldehyde (1 equivalent) and N-methyl hydrazine (0.5-1.5 equivalent).
9. The process for the preparation of the ervatinib intermediate 3- (1-methyl-1H-pyrazol-4-yl) -6-quinoxalinamine according to claim 1, characterized in that: the solvent of the condensation reaction is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, toluene or water; the temperature of the condensation reaction is 50-120 ℃.
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