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877399-52-5 Structure

877399-52-5 Structure
IdentificationBack Directory



PF 2341066
Crizotinib (PF2341066)
PF-02341066 Crizotinib
k-ras(g12c) inhibitor 6 NA Crizotinib
2-PyridinaMine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-
[3-[[(R)-1-(2,6-Dichloro-3- fluorophenyl)ethyl]oxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-yl]aMine

[Molecular Formula]

[MDL Number]

[MOL File]

[Molecular Weight]

Chemical PropertiesBack Directory
[Melting point ]

192 °C
[Boiling point ]

599.2±50.0 °C(Predicted)
[density ]

1.47±0.1 g/cm3(Predicted)
[storage temp. ]

room temp

[form ]

[color ]

white to tan
[CAS DataBase Reference]

Hazard InformationBack Directory
[Chemical Properties]

White Solid

PF-2341066 (Crizotinib) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM, respectivley

A potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). A potential antitumor agent.

Crizotinib is a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). Crizotinib is a potential antitumor agent.

ChEBI: A 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)pyrazol-4-yl]pyridin-2-amine that has R configuration at the chiral centre. The active enantiomer, it acts as a kinase inhibitor and is used for the treatment of patients wi h locally advanced or metastatic non-small cell lung cancer (NSCLC)

In August 2011, the United States FDA approved crizotinib (PF- 02341066) for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). Crizotinib is a dual ATP competitive inhibitor of tyrosine kinases c-MET (Mesenchymal-Epithelial Transition Factor) kinase (cellular IC50=8 nM) and ALK (cellular IC50=20 nM), both of which are important targets for cancer chemotherapy. When crizotinib was tested for selectivity versus other kinases it was found to have enzyme IC50's within 100-fold multiples of c-MET for 13 of the 120 kinases tested. In cellular assays, crizotinib was found to inhibit RON (recepteur d’origine nantais) kinase with a 10-fold selectivity window over c-MET.

Pfizer (United States)

PF-2341066 (Crizotinib) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM, respectivley

Crizotinib is a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). Crizotinib is a potential antitumor agent.

A potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). A potential antitumor agent.

Crizotinib (Xalkori(R), Pfizer), approved in 2011, was the first approved inhibitor targeting anaplastic lymphoma kinase (ALK). ROS protooncogene 1-encoded kinase (ROS1) of the tyrosine kinase insulin receptor class and MET proto-oncogene-encoded kinase of the hepatocyte growth factor receptor (HGFR) class are other kinases targeted by crizotinib.When approved in 2011, crizotinib was the first drug specifically targeting NSCLC patients. However, resistance to crizotinib was usually observed in approximately 8 months after initial application and more than half of crizotinib-treated patients experienced gastrointestinal side effects. In 2016,crizotinib was additionally approved for ROS1-positive NSCLC by FDA.
[Brand name]

[Clinical Use]

More recent studies have shown that patients with MET amplification and no ALK rearrangement treated with crizotinib have responded well in NSCLC and squamous cell lung carcinoma.
Crizotinib is a potent and selective mesenchymal epithelial transition factor/anaplastic lymphoma kinase (cMET/ALK) inhibitor. Marketed under the brand name Xalkori, crizotinib was discovered and developed by Pfizer and is approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) that is caused by the echinoderm microtubule associated proteinlike 4 (EML4) mutation of ALK. Crizotinib is also undergoing clinical evaluation against additional cancers which express the ALK mutation, such as advanced disseminated anaplastic large-cell lymphoma and neuroblastoma.
[Chemical Synthesis]

Several synthetic routes for the preparation of crizotinib have been reported, each employing a very similar convergent strategy. The synthesis utilized to prepare over 100 kg is described in the scheme.

Mesylation of tert-butyl-4-hydroxypiperidine-1-carboxylate (116) followed by displacement with 4-iodopyarazole (117) provided iodopyrazine 118 in 50–60% overall yield for the two steps. Reaction of iodide 118 with i-PrMgCl furnished the corresponding Grignard reagent, which was quenched with borolane 119 to give the arylboronate 120 in 70–80% yield after crystallization from ethanol/water. The Suzuki coupling partner of 120 (bromide 126) was prepared in several steps starting with enzymatic reduction of 2,6-dichloro-3-fluoroacetophenone (121) using an engineered ketoreductase process, providing alcohol 122 in 94% yield and in >99% ee. Mitsunobu reaction with 3-hydroxy-2-nitropyridine (123) provided nitropyridine 124 in 80–85% yield after crystallization from ethanol and with no loss in enantiopurity. Chemoselective reduction of the nitro group was accomplished through hydrogenation using 10% sponge-nickel catalyst to give amine 125 in 95% yield after crystallization from methanol. Regioselective bromination of 125 using NBS in CH3CN/CH2Cl2, followed by a bisulfate quench and Et3N wash (to purge residual succinimide) and subsequent crystallization from methanol provided Suzuki- Miyaura coupling partner 126 in 80–85% yield. Coupling of arylbromide 126 with arylboronate 120 was accomplished using 0.8 mol % PdCl2(dppf)CH2Cl2 as the catalyst, followed by treatment with cysteine on silica-alumina to purge residual palladium. Crystallization of the resulting mixture from heptanes provided the coupled product in 76–80% yield, which upon acid-promoted removal of the Boc protecting group and crystallization from CH3CN/H2O produced crizotinib (X) in 75–80% yield.
Safety DataBack Directory
[Safety Statements ]


UN 3077 9 / PGIII
[WGK Germany ]

[HazardClass ]

[HS Code ]

Questions And AnswerBack Directory
[Biological Activity]

Potent inhibitor of c-MET and anaplastic lymphoma kinase (ALK) (cell IC50 values are 8.0 and 20 nM respectively). Selective for c-MET and ALK against >120 different kinases. Displays antitumor efficacy in multiple tumor models; inhibits c-MET-dependent proliferation, migration and invasion of human tumor cells in vitro. Orally bioavailable.
[Mechanism of action]

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in the activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrates concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumor cell lines, and also demonstrates antitumor activity in mice bearing tumor xenografts that express EML4-or NPM-ALK fusion proteins or c-Met.Crizotinib is a multitargeted small molecule tyrosine kinase inhibitor, which had been originally developed as an inhibitor of the mesenchymal epithelial transition growth factor (c-MET); it is also a potent inhibitor of ALK phosphorylation and signal transduction. This inhibition is associated with G1-S phase cell cycle arrest and induction of apoptosis in positive cells in vitro and in vivo. Crizotinib also inhibits the related ROS1 receptor tyrosine kinase.
[side effects]

crizotinib (Xalkori) is an oral receptor tyrosine kinase inhibitor indicated for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). Common side effects with Xalkori use include upper respiratory infection, nausea, vomiting, stomach pain, decreased appetite, insomnia, dizziness, tired feeling, diarrhea, constipation, rash or itching, cold symptoms (stuffy nose, sneezing, sore throat), numbness or tingling, or swelling in your hands or feet.
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