- Bosutinib 1, 4-piperazine dimer impurity and preparation method thereof
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The invention discloses a bosutinib 1, 4-piperazine dimer impurity and a synthesis process thereof, the synthesis process is simple, the purity is high, raw materials are simple and easy to obtain, the purity of the prepared finished product can reach 96%
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Paragraph 0034-0069
(2021/04/07)
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- A kind of deuterium generation 3-cyano-quinoline compound, a pharmaceutically acceptable composition, preparation method and its use
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Disclosed in the invention are a deuterated 3-cyano quinoline compound or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphic substances, metabolites etc., and a pharmaceutical composition containing such compounds, and the use of these compounds or compositions in the preparation of drugs for treating or preventing tumours, especially drugs such as protein kinase inhibitors. Compared with the prior art, the compounds of the present invention have the clear advantages of properties such as plasma drug concentration, half-life, clearance, microsomal stability, bioavailability or enzyme inhibition and the like, and thus can more effectively inhibit the activities of more than one protein kinase and/or inhibit the growth of tumuor cells.
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- New Synthetic Process for Bosutinib
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A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).
- Mao, Yongjun,Zhu, Chunping,Kong, Ziyang,Wang, Jiao,Zhu, Guoqing,Ren, Xinfeng
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p. 3133 - 3138
(2015/10/19)
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- A new and practical synthesis of bosutinib
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New and improved synthetic route of bosutinib is described on a decagram scale. An intramolecular cyclization of 3-amino-2-(2-bromobenzoyl)-acrylonitrile (22) in K2CO3/DMF condition to form the key 3-cyano-4-hydroxyquinoline intermediate (13) is adopted as the key step. Bosutinib is obtained in 13.7% yield over ten steps and 98.9% purity (HPLC), which make it as a process of cost effective, environmentally friendly and feasible for scale-up operation.
- Wang, Han,Zhu, Chunping,Zhu, Guoqing,Tian, Xin,Shen, Yongjia,Mao, Yongjun
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p. 2806 - 2813
(2015/02/19)
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- Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid
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This paper reports a novel synthesis of bosutinib starting from 3-methoxy-4-hydroxybenzoic acid. The process starts with esterification of the starting material, followed by alkylation, nitration, reduction, cyclization, chlorination and two successive amination reactions. The intermediates and target molecule were characterized by 1H-NMR, 13C-NMR, MS and the purities of all the compounds were determined by HPLC.
- Yin, Xiao Jia,Xu, Guan Hong,Sun, Xu,Peng, Yan,Ji, Xing,Jiang, Ke,Li, Fei
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experimental part
p. 4261 - 4266
(2010/09/18)
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- Process for preparation of 4-amino-3-quinolinecarbonitriles
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This invention discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising combining an amine compound with a cyanoacetic acid and an acid catalyst to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline in an alcoholic solvent and a trialkylorthoformate to yield a 3-amino-2-cyanoacrylamide; combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile and also discloses a process for the preparation of a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile comprising combining a disubstituted 3-amino thiophene with a cyanoacetamide and trialkylorthoformate in an alcoholic solvent to obtain a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile and also discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile by combining an amine compound with a cyanoacetic acid and a peptide coupling reagent to obtain a suspension; filtering the suspension to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline, an alcoholic solvent, and triethylorthoformate to yield a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride to yield a 4-amino-3-quinolinecarbonitrile.
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Page/Page column 11-12
(2010/02/10)
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- Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity
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Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino] -6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM) several additional analogues were prepared. Optimization of the C-4 anilino group of la led to lc which contains a 2,4-dichloro-5-methoxy- substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors and the propoxy group of 2c was preferred over ethoxy butoxy or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a which had an IC50 of 1.2 nM in the Src enzymatic assay an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a which had higher 1 and 4 h plasma levels than 2c effectively inhibited tumor growth in xenograft models.
- Boschelli,Ye,Wang,Dutia,Johnson,Wu,Miller,Powell,Yaczko,Young,Tischler,Arndt,Discafani,Etienne,Gibbons,Grod,Lucas,Weber,Boschelli
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p. 3965 - 3977
(2007/10/03)
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