- Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow
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Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I) afforded the desired product (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II.
- Chen, Jianli,Cheng, Pengfei,Su, Weike,Xie, Xiaoxuan,Xu, Feng,Yu, Zhiqun
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- Fit-for-purpose development of the enabling route to crizotinib (PF-02341066)
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A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.
- De Koning, Pieter D.,McAndrew, Douglas,Moore, Robert,Moses, Ian B.,Boyles, David C.,Kissick, Kyle,Stanchina, Corey L.,Cuthbertson, Timothy,Kamatani, Asayuki,Rahman, Leera,Rodriguez, Rick,Urbina, Armando,Sandovalnee Accacia, Alison,Rose, Peter R.
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- Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
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Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or –overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib.
- Berger, Walter,Bielec, Bjoern,Heffeter, Petra,Keppler, Bernhard K.,Kowol, Christian R.,Schueffl, Hemma,Terenzi, Alessio
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- Mild and Robust Stille Reactions in Water using Parts Per Million Levels of a Triphenylphosphine-Based Palladacycle
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An inexpensive and new triphenylphosphine-based palladacycle has been developed as a pre-catalyst, leading to highly effective Stille cross-coupling reactions in water under mild reaction conditions. Only 500–1000 ppm of Pd suffices for couplings involving a variety of aryl/heteroaryl halides with aryl/hetaryl stannanes. Several drug intermediates can be prepared using this catalyst in aqueous nanoreactors formed by 2 wt % Brij-30 in water.
- Takale, Balaram S.,Thakore, Ruchita R.,Casotti, Gianluca,Li, Xaiohan,Gallou, Fabrice,Lipshutz, Bruce H.
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supporting information
p. 4158 - 4163
(2021/02/01)
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- Reactive Oxygen Species (ROS)-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
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Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients' quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with H2O2 and their stability in cell culture medium and serum. Finally, the biological activity of the prodrugs was investigated in three cancer cell lines and revealed a good correlation between activity and intrinsic H2O2 levels of the cells for prodrug A. Furthermore, the activity of this prodrug was distinctly reduced in a non-malignant, c-MET expressing human lung fibroblast (HLF) cell line.
- Ahmed, Esra,Bielec, Bjoern,Heffeter, Petra,Keppler, Bernhard K.,Kowol, Christian R.,Poetsch, Isabella
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- Palladium removal method for crizotinib intermediate
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The invention discloses a method for removing palladium from a crizotinib intermediate. The method comprises the following steps: adding a heavy metal ion remover into a palladium-containing reactionsolution; after the remover is separated, a solid is sep
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Paragraph 0031-0051
(2020/07/15)
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- Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2
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Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
- Wang, Wanqi,Diao, Yanyan,Li, Wenjie,Luo, Yating,Yang, Tingyuan,Zhao, Yuyu,Qi, TianTian,Xu, Fangling,Ma, Xiangyu,Ge, Huan,Liang, Yingfan,Zhao, Zhenjiang,Liang, Xin,Wang, Rui,Zhu, Lili,Li, Honglin,Xu, Yufang
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p. 1507 - 1513
(2019/04/17)
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- Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions
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Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents.
- Markovic, Tim,Murray, Philip R.D.,Rocke, Benjamin N.,Shavnya, Andre,Blakemore, David C.,Willis, Michael C.
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p. 15916 - 15923
(2018/11/23)
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- Preparation method of crizotinib intermediate
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The invention provides a preparation method of a crizotinib intermediate. The preparation method is characterized by adopting a porphyrin palladium catalyst to enable (R)-5-bromine-3-(1-(2,6-dichloro-3-fluorophenyl)ethyoxyl)pyridine-2-amine and 1-(N-Boc-4
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Paragraph 0034; 0041; 0042; 0045; 0048; 0051; 0054
(2018/11/22)
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- Preparation method for crizotinib intermediate
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The invention discloses a preparation method for a crizotinib intermediate, specifically to a method for removing the residues of heavy metal palladium in a compound as shown in a formula (I) which isdescribed in the specification, i.e., the crizotinib in
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Paragraph 0021; 0022; 0023
(2018/09/28)
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- Synthetic method of crizotinib
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The invention relates to the technical field of organic synthesis, and especially discloses a synthetic method of crizotinib. The route of the synthetic method is designed in such a way that less steps are required in the synthesis and less side reactions
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- Preparation method of Crizotinib or deuterated Crizotinib
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Belonging to the field of pharmaceutical compounds, the invention relates to a preparation method of Crizotinib or deuterated Crizotinib. The preparation method of Crizotinib or deuterated Crizotinib includes: 1) preparation of a formula III compound; 2)
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Paragraph 0049; 0051; 0056
(2017/10/24)
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- Crizotinib intermediate, preparation method and crizotinib preparation method
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The invention relates to a crizotinib intermediate, a preparation method and a crizotinib preparation method, in particular to an intermediate of crizotinib which has the structure of a formula (CZT-5) as shown in the description and the structure of a formula (CZT-9) as shown in the description, a preparation method of the intermediate and a preparation method of a crizotinib with the structure of a formula (CZT-11). The method provided by the invention has the characteristics of short route, high yield, easiness in acquisition of raw materials, high reaction selectivity and the like, chiral resolution is not required in a synthetic process, the utilization rate of the raw materials is increased, the path costs are low, and therefore, the method can meet requirements of large-scale industrial production.
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- Combination of a C-Met antagonist and an aminoheteroaryl compound for the treatment of cancer
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The invention also relates to a composition comprising an antibody antagonist to c-Met and an aminoheteroaryl compound, particularly as a medicament. The present invention also comprises a pharmaceutical composition comprising said anti c-Met antibody and said aminoheteroaryl compound as combination products for simultaneous, separate or sequential use. The invention relates to the use of the composition of the invention for the treatment of cancer in a mammal.
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- Preparation method of crizotinib
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The invention discloses a preparation method of crizotinib. An intermediate (V) is prepared through boric acid condensation, so that the defects of instable borate serving as a raw material, complexity in operation, low yield and large-scale production difficulty in the prior art are overcome. The preparation method is low in cost, simple and convenient to operate, high in yield, good in optical purity and suitable for large-scale production.
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- An anti-tumor molecule targeting drug [...] process for the synthesis of
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The invention provides a synthetic process method for a novel antineoplastic molecular targeted drug of crizotinib, and relates to the resolution process optimization of chiral isomers of a crizotinib precursor and the recycling of by-products. The method adopts a catalyzing resolution method that Boc-L-proline, namely, N-(tert-butoxycarbonyl)-L-proline) is combined with a catalyst of p-toluenesulfonic acid and a condensating agent of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to split 1-(2,6-dichloro-3-fluorophenyl)ethanol racemate into S-type alcohol and R-type alcohol, and a resolution by-product mixture is subjected to hydrolysis and configuration transition to obtain the (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol; the total yield is improved to 76% from 30%, the time is shortened, pollution is reduced, and application to industrialized production is easy.
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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Paragraph 0267; 0268
(2016/08/17)
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- Crizotinib Preparation Method
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The present invention relates to the technical field of medicine and organic synthesis, particularly to a method for preparing crizotinib. The method comprises the compound of formula b and the compound of formula e undergoing Suzuki coupling reaction to
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Paragraph 0036-0037
(2015/11/16)
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- PROCESS FOR THE PREPARATION OF PYRAZOLE SUBSTITUTED AMINOHETEROARYL COMPOUNDS
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The present invention relates to an improved process for the preparation of pyrazole substituted aminoheteroaryl compounds. More particularly, the present invention provides highly pure 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4- yl)pyridin-2-amine, its intermediates and preparation thereof. The process of the present invention is simple, convenient, does not use expensive chemicals and avoids use of tedious purification techniques. Invention also provides process intermediates, useful not only in the synthesis, but also useful for providing desired compound with high purity.
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- PYRIDINE COMPOUNDS AS INHIBITORS OF KINASE
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Disclosed are pyridines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
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Page/Page column 23; 24
(2013/04/10)
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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- Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
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Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- Cui, J. Jean,Tran-Dubé, Michelle,Shen, Hong,Nambu, Mitchell,Kung, Pei-Pei,Pairish, Mason,Jia, Lei,Meng, Jerry,Funk, Lee,Botrous, Iriny,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Padrique, Ellen,Alton, Gordon,Timofeevski, Sergei,Yamazaki, Shinji,Li, Qiuhua,Zou, Helen,Christensen, James,Mroczkowski, Barbara,Bender, Steve,Kania, Robert S.,Edwards, Martin P.
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p. 6342 - 6363
(2011/11/05)
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- AMINOHETEROARYL COMPOUNDS AS FOR THE TREATMENT OF DISEASES MEDIATED BY C-MET KINASE ACTIVITY
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Compounds of formula (I), are inhibitors of c-Met kinase activity, useful inter alia in the treatment of hyperproliferative diseases: wherein X is -N= or -CH=; ring A is optionally substituted mono- or bi-cyclic aryl or heteroaryl having from 5 to 12 ring
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Page/Page column 43-44
(2008/12/05)
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- Method of Treating Abnormal Cell Growth
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The present invention relates to the use of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, a novel c-Met/HGFR inhibitor, for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer.
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- Polymorphs of a C-Met/Hgfr Inhibitor
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This invention relates to polymorphs of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such salts and polymorphs, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.
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Page/Page column 7
(2009/01/20)
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- PYRAZOLE-SUBSTITUTED AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Compounds of formula (1) are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 132
(2010/10/20)
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