CN108623521B - Preparation method of lenvatinib - Google Patents
Preparation method of lenvatinib Download PDFInfo
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- CN108623521B CN108623521B CN201810238589.7A CN201810238589A CN108623521B CN 108623521 B CN108623521 B CN 108623521B CN 201810238589 A CN201810238589 A CN 201810238589A CN 108623521 B CN108623521 B CN 108623521B
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960003784 lenvatinib Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 229940126062 Compound A Drugs 0.000 claims description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- -1 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide Compound Chemical class 0.000 description 2
- GKACWNQKWMLZOV-UHFFFAOYSA-N 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide Chemical compound C1=C(C(N(=O)=O)=CC=C1OC1=C2C(=NC=C1)C=C(C(C(=O)N)=C2)OC)Cl GKACWNQKWMLZOV-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 240000006570 Euonymus japonicus Species 0.000 description 1
- 235000016796 Euonymus japonicus Nutrition 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 101150077555 Ret gene Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention relates to a preparation method of lenvatinib, and belongs to the field of pharmaceutical chemicals. The preparation method of the lenvatinib is a brand new preparation scheme, and a target compound meeting the requirement can be obtained from any intermediate. The method has the advantages of short steps, simple reaction operation, safety, reliability, high yield, low cost, high purity, less pollution, simple operation and the like. The total yield of the Levatinib can reach about 84%, and the purity can reach 99.7%.
Description
Technical Field
The invention relates to a preparation method of lenvatinib, and belongs to the field of pharmaceutical chemicals.
Background
Lenvatinib (Lenvatinib) is an oral effective multi-kinase inhibitor developed by Euonymus japonicus, mainly acts on a plurality of targets such as c-Kit, Ret, VEGFR-2 and the like, and is used for treating solid tumors such as glioma, thyroid tumor, renal cancer, liver cancer, ovarian cancer and the like. Us FDA orphan drug was obtained 2 months 2013 and was clinically used for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced papillary thyroid carcinoma.
The chemical name of lenvatinib is: 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide having the structure:
the preparation of lenvatinib is disclosed in the prior art, for example CN1478078 and CN1878751, EP1683785a1, EP1698623a1, EP1797881a1, US7683172a1, etc. At present, A, B are mainly used for preparing the medicine.
The route A is as follows: the compound d and 4-amino-3-chlorophenol (compound e) are firstly condensed to prepare a compound g, the compound g reacts with phenyl chloroformate, and then reacts with cyclopropylamine to generate urea so as to obtain the lenvatinib.
The route B is as follows: and (3) reacting the compound e with phenyl chloroformate, then carrying out urea reaction with cyclopropylamine to obtain a compound k, and finally condensing the compound k and the compound d to obtain the lenvatinib.
Considering the two synthetic routes A and B, although lenvatinib can be prepared, in the A, B route, the amino group of the raw material d and the amino group of the raw material e are not protected, and impurities are generated; in the route B, phenyl chloroformate with certain toxicity is used as a raw material, and phenol with high toxicity is generated in subsequent reactions. The total yield of lenvatinib is about 70% and the purity can reach about 99.5% as reported in the prior art. Therefore, the search for a new preparation method of lenvatinib, which can simplify the process, reduce the environmental pollution and reduce the production cost, has very important practical significance.
Disclosure of Invention
In order to solve the above problems, the first object of the present invention is to provide a method for preparing lenvatinib, the synthetic route of the method is as follows:
in one embodiment of the present invention, the method comprises the following specific steps:
(1) heating and stirring the compound A and the compound B under the alkaline condition and in the presence of a solvent to generate a compound C;
(2) reducing the nitro group of the compound C into amino group by hydrogen treatment in the presence of a catalyst and a solvent to generate a compound D;
(3) reacting the compound D with a compound E1 or a compound E2 in the presence of a solvent to generate lenvatinib;
In one embodiment of the present invention, the molar ratio of the compound a to the compound B in the step (1) is 1:1 to 2.
In one embodiment of the present invention, the molar ratio of the compound a to the compound B in the step (1) is 1:1 to 1.2.
In one embodiment of the present invention, the base in step (1) is an organic base or an inorganic base, including but not limited to N, N' -diisopropylethylamine, trimethylethylenediamine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, cesium carbonate, potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium fluoride, potassium tert-butoxide, sodium ethoxide or sodium methoxide.
In one embodiment of the present invention, the base is used in a molar ratio of 1:2 to 5 relative to the compound a.
In one embodiment of the present invention, the base is used in a molar ratio of 1:2.5 to 3 relative to the compound a.
In one embodiment of the present invention, the solvent in step (1) is one or more of N, N '-Dimethylformamide (DMF), N' -dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, pyridine, dioxane, tetrahydrofuran, or N-methylpyrrolidone.
In one embodiment of the present invention, the reaction temperature in the step (1) is 60 to 100 ℃.
In one embodiment of the present invention, the reaction temperature in the step (1) is 85 to 95 ℃.
In one embodiment of the present invention, the catalyst in the step (2) is palladium, platinum, rhodium or nickel.
In one embodiment of the present invention, the catalyst in the step (2) is platinum oxide, palladium black or palladium carbon.
In one embodiment of the present invention, the amount of the catalyst used in the step (2) is 0.05 to 1w/w based on the weight of the compound C.
In one embodiment of the present invention, the solvent in step (2) is methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, ethyl acetate, DMF, water or a mixed solvent thereof.
In one embodiment of the present invention, the reaction temperature in the step (2) is 0 to 65 ℃.
In one embodiment of the present invention, the reaction temperature in the step (2) is 10 to 30 ℃.
In one embodiment of the present invention, the reaction pressure in the step (2) is 0.1 to 3 MPa.
In one embodiment of the present invention, the reaction pressure in the step (2) is 0.5 to 1.5 MPa.
In one embodiment of the present invention, when the compound D and E1 are reacted in step (3), the reaction is performed under basic conditions, and the base includes, but is not limited to, N' -diisopropylethylamine, trimethylethylenediamine, 1, 8-diazabicycloundec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, cesium carbonate, potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium fluoride, potassium tert-butoxide, sodium ethoxide or sodium methoxide.
In one embodiment of the invention, the molar ratio of the compound D to the base used is from 1:0.5 to 3, preferably from 1:1.5 to 2.
In one embodiment of the present invention, in the step (3), when the compound D is reacted with E1, the solvent is one or more of N, N '-Dimethylformamide (DMF), N' -dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, pyridine, dioxane, tetrahydrofuran, and N-methylpyrrolidone.
In one embodiment of the invention, the molar ratio of compound D to compound E1 is 1: 1-2.
In one embodiment of the invention, the molar ratio of compound D to compound E1 is 1:1 to 1.5.
In one embodiment of the invention, the reaction temperature is from 50 ℃ to 180 ℃, preferably from 80 ℃ to 90 ℃.
In one embodiment of the present invention, when the compound D and E1 are reacted in the step (3), the molar ratio of the compound D to the compound E2 is 1:1-2, preferably 1: 1-1.2.
In one embodiment of the invention, the reaction temperature is from-25 ℃ to 40 ℃, preferably from 20 ℃ to 25 ℃.
In one embodiment of the present invention, the solvent is one or more of tetrahydrofuran, dichloroethane, ethyl acetate, n-hexane, petroleum ether, dichloromethane, cyclohexane, butyl acetate.
The invention has the advantages and effects that:
the preparation method of the invention has the following advantages: simple and easy operation, simple and easily obtained raw materials, low energy consumption, high yield, good quality and convenient industrial production. The total yield of the Levatinib can reach about 84%, and the purity can reach 99.7%.
Drawings
Figure 1 is a liquid phase diagram of lenvatinib.
Detailed description of the preferred embodiments
The method for calculating the yield comprises the following steps: after the product was dried, the yield was 100% actual/theoretical yield.
HPLC determination method: waters hplc, column (C18250 × 4.6 × 4um), column temperature (30 ℃), acetonitrile: methanol: 75:25, flow rate 0.5 ml/min.
In the following examples, unless otherwise indicated, the test procedures described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.
Example 1: preparation of 4- (3-chloro-4-nitrophenoxy) -7-methoxyquinoline-6-carboxamide Compound C
A (23.6g, 0.1mol), B (19.4g, 0.11mol) and cesium carbonate (91.2g, 0.28mol) were added to 250ml of dimethyl sulfoxide, and the mixture was stirred with heating at 90 ℃ for 10 hours. The reaction solution was cooled to room temperature, poured into 750ml of water, stirred for 30 minutes, filtered and dried to obtain 35.36g of compound (C). (yield 94.6%)
Example 2: preparation of 4- (3-chloro-4-nitrophenoxy) -7-methoxyquinoline-6-carboxamide Compound C
A (23.6g, 0.1mol), B (20.83g, 0.12mol) and cesium carbonate (97.75g, 0.3mol) were added to 250ml of dimethyl sulfoxide, and the mixture was stirred with heating at 95 ℃ for 8 hours. The reaction solution was cooled to room temperature, poured into 750ml of water, stirred for 30 minutes, filtered and dried to obtain 34.57g of the title compound (C). (yield 92.5%)
Example 3: preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide Compound D
Compound C (10g, 26.7mmol) was dissolved in methanol (50ml), 10% Pd/C (1.0g) was added, and the solution was washed with H2Displacement reactionIs reacted four times in H2Stirring overnight at room temperature under ambient (0.5MPa), TLC analysis showed complete reaction, reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give 9.114g of Compound D in 99.3% yield.
Example 4: preparation of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide Compound D
Compound C (15g, 26.7mmol) was dissolved in methanol (75ml) and Raney Ni (1.5g) was added over H2Four times replacement of the reaction system in H2Stirring overnight at room temperature under ambient (1.0MPa), TLC analysis to complete the reaction, filtering the reaction solution with celite, and concentrating the filtrate under reduced pressure to give 9.132g of Compound D in 99.5% yield.
Example 5: preparation of lenvatinib
The method comprises the following steps: compound D (1.03g, 3mmol), compound E1(0.39g, 3mmol) and DMF (10ml) were added to the reaction vessel and dissolved with stirring at 25 ℃ and after complete dissolution N, N' -diisopropylethylamine (0.78g, 6mmol) was added and the reaction was slowly warmed to 80 ℃ and monitored by TLC for reaction completion. Water (50ml) was added and stirred, filtered, the filter cake washed with water and dried, resulting in lenvatinib (1.14g) in 89.3% yield.
Example 6: preparation of lenvatinib
The method comprises the following steps: compound D (1.03g, 3mmol), compound E1(0.46g, 3.6mmol) were added to the reaction vessel followed by DMF (10ml) and dissolved with stirring at 25 deg.C, after complete dissolution N, N' -diisopropylethylamine (0.78g, 6mmol) was added and the reaction was slowly warmed to 85 deg.C and monitored by TLC for reaction completion. Water (50ml) was added, stirred, filtered, the filter cake washed with water and dried, resulting in delavatinib (1.12g) with a yield of 87.6%.
Example 7: preparation of lenvatinib
The second method comprises the following steps: compound D (10.29g, 30mmol) was added to dichloromethane (100ml), compound E2(2.49g, 30mmol) was added, stirring was carried out at 25 ℃ for 2 days, and filtered to give lenvatinib (11.12g) in 86.8% yield.
Example 8: preparation of lenvatinib
The second method comprises the following steps: compound D (10.29g, 30mmol) was added to dichloromethane (100ml), compound E2(2.74g, 33mmol) was added, stirring was carried out at 20 ℃ for 3 days, and filtered to give lenvatinib (11.12g) in 86.8% yield.
The overall yield of lenvatinib can reach about 84%, and the purity can reach 99.7%.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (9)
1. The preparation method of lenvatinib is characterized in that the synthetic route of the method is as follows:
the method comprises the following specific synthetic steps:
(1) heating and stirring the compound A and the compound B under the alkaline condition and in the presence of a solvent to generate a compound C; the base is cesium carbonate; the solvent is dimethyl sulfoxide;
(2) reducing the nitro group of the compound C into amino group by hydrogen treatment in the presence of a catalyst and a solvent to generate a compound D; the catalyst is palladium or nickel; the solvent is methanol;
(3) reacting the compound D with a compound E1 or a compound E2 in the presence of a solvent to generate lenvatinib; when the compound D and E1 are reacted, a solvent is DMF, the reaction is carried out under the alkaline condition, and the base is N, N' -diisopropylethylamine; when the compound D is reacted with E2, the solvent is dichloromethane;
2. The method according to claim 1, wherein the molar ratio of the compound A to the compound B in the step (1) is 1: 1-2.
3. The method according to claim 1, wherein the base is used in a molar ratio of 1:2 to 5 relative to the compound A.
4. The method according to claim 1, wherein the catalyst is used in an amount of 0.05 to 1w/w based on the weight of the compound C.
5. The method according to claim 1, wherein the reaction of compound D with E1 in step (3) is carried out under alkaline conditions, and the molar ratio of compound D to the base used is 1: 0.5-3.
6. The method according to claim 5, wherein the molar ratio of compound D to the base used is 1: 1.5-2.
7. The method according to claim 1, wherein the molar ratio of compound D to compound E1 is 1: 1-2.
8. The method according to claim 1, wherein in the step (3), when the compound D is reacted with the compound E2, the molar ratio of the compound D to the compound E2 is 1: 1-2.
9. The method according to claim 8, wherein the molar ratio of the compound D to the compound E2 is 1: 1-1.2.
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