877399-51-4

Basic information

• Product Name: (R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
• Synonyms: 1-Piperidinecarboxylic acid,4-[4-[6-aMino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]-1H-pyrazol-1-yl]-, 1,1-diMethylethyl ester;4-[4-[6-Amino-5-[[(R)-1-(2,6-dichloro-3-fluorophenyl)ethyl]oxy]pyridin-3-yl]pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester;(R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl);tert-butyl 4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;(R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine -3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;(R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;tert-butyl (R)-4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
• CAS NO: 877399-51-4
• Molecular Formula: C26H30Cl2FN5O3
• Molecular Weight: 550.4525032
• Mol File: 877399-51-4.mol

Chemical Properties

• Melting Point: 150℃
• Boiling Point: 654.7±55.0 °C(Predicted)
• Appearance: /
• Density: 1.38±0.1 g/cm3 (20 oC 760 Torr), Calc.*
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 7.11±0.10(Predicted)
• CAS DataBase Reference: (R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(877399-51-4)
• EPA Substance Registry System: (R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(877399-51-4)

Safety Data

• Hazardous Substances Data: 877399-51-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Research:
(R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate is used as a research compound for exploring its potential as a therapeutic agent. Its unique molecular structure and chiral center provide opportunities for studying structure-activity relationships, which are crucial for the development of novel drugs with targeted biological activities.
Used in Drug Development:
In the pharmaceutical industry, (R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate is utilized as a lead compound in drug development. Its complex structure and functional groups offer a foundation for the design and optimization of new drugs aimed at treating various medical conditions. (R)-tert-butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate's potential as a therapeutic agent makes it a promising candidate for further research and development efforts.

Upstream product

• 74115-13-2 5-bromopyridine-3-ol 
• 691872-15-8 5-bromo-3-hydroxy-2-nitropyridine 
• 290835-85-7 2',6'-dichloro-3'-fluoroacetophenone 
• 1331786-34-5 (±)-bis(Boc)-3-(1-(2,6-dichloro-3-fluoropheny)ethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine 
• 1331786-33-4 (±)-bis(Boc)-5-bromo-3-(1-(2,6-dichloro-3-fluoropheny)ethoxy)pyridin-2-amine 
• 756503-69-2 (±)-5-bromo-3-(1-(2,6-dichloro-3-fluoropheny)ethoxy)pyridin-2-amine 
• 756520-67-9 (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine 
• 756521-08-1 (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine 
• 756520-66-8 1-(2,6-dichloro-3-fluorophenyl)ethanol 
• 877399-08-1 (±)-3-(1-(2,6-dichloro-3-fluoropheny)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 
• 877399-50-3 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 
• 756509-08-7 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1H-pyrazol-4-yl)pyridin-2-amine 
• 141699-59-4 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate 
• 1448326-33-7 5-bromo-3-[1 (R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine 

Downstream Products

• 877399-52-5 crizotinib 

Relevant articles and documents

Mild and Robust Stille Reactions in Water using Parts Per Million Levels of a Triphenylphosphine-Based Palladacycle

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.

Reactive Oxygen Species (ROS)-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib

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.

Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib

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.

Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow

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.

Palladium removal method for crizotinib intermediate

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

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

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.

Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions

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.

Preparation method of crizotinib intermediate

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

Preparation method for crizotinib intermediate

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

Synthetic method of crizotinib

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