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Crizotinib

CAS No.
877399-52-5
Chemical Name:
Crizotinib
Synonyms
Xalkori;Crizotini;3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-2-aMinopyridine;CS-164;Crozotinib;Crizotinib;PF 2341066;Crizotanib;PF-02341066;(R)-Crizotinib
CBNumber:
CB12473904
Molecular Formula:
C21H22Cl2FN5O
Molecular Weight:
450.34
MDL Number:
MFCD12407409
MOL File:
877399-52-5.mol
MSDS File:
SDS
Last updated:2024-12-02 17:19:06

Crizotinib Properties

Melting point 192 °C
Boiling point 599.2±50.0 °C(Predicted)
Density 1.47±0.1 g/cm3(Predicted)
storage temp. room temp
solubility Soluble in DMSO (up to 25 mg/ml with warming) or in Ethanol (up to 25 mg/ml with warming)
pka 9.81±0.10(Predicted)
form powder
color white to tan
Stability Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months.
InChIKey KTEIFNKAUNYNJU-GFCCVEGCSA-N
SMILES C1(N)=NC=C(C2=CN(C3CCNCC3)N=C2)C=C1O[C@@H](C1=C(Cl)C=CC(F)=C1Cl)C
CAS DataBase Reference 877399-52-5
FDA UNII 53AH36668S
NCI Dictionary of Cancer Terms crizotinib; Xalkori
NCI Drug Dictionary crizotinib
ATC code L01ED01

Pharmacokinetic data

Protein binding 91%
Excreted unchanged in urine 2.3%
Volume of distribution 1772 Litres
Biological half-life 42 / -

SAFETY

Risk and Safety Statements

Symbol(GHS)  GHS hazard pictogramsGHS hazard pictogramsGHS hazard pictograms
GHS07,GHS08,GHS09
Signal word  Warning
Hazard statements  H317-H319-H341-H400
Precautionary statements  P201-P273-P280-P302+P352-P305+P351+P338-P308+P313
Safety Statements  24/25
RIDADR  UN 3077 9 / PGIII
WGK Germany  3
HazardClass  IRRITANT
HS Code  29333990
NFPA 704
0
2 0

Crizotinib price More Price(56)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich PZ0191 Crizotinib ≥98% (HPLC) 877399-52-5 5MG $132 2024-03-01 Buy
Cayman Chemical 12087 Crizotinib ≥98% 877399-52-5 5mg $114 2023-06-20 Buy
Cayman Chemical 12087 Crizotinib ≥98% 877399-52-5 10mg $197 2023-06-20 Buy
Cayman Chemical 12087 Crizotinib ≥98% 877399-52-5 50mg $87 2024-03-01 Buy
Tocris 4368 Crizotinib ≥99%(HPLC) 877399-52-5 10 $281 2021-12-16 Buy
Product number Packaging Price Buy
PZ0191 5MG $132 Buy
12087 5mg $114 Buy
12087 10mg $197 Buy
12087 50mg $87 Buy
4368 10 $281 Buy

Crizotinib Chemical Properties,Uses,Production

Description

Crizotinib is an oral ALK/ROS1/MET/RON inhibitor approved by the U.S. Food and Drug Administration. Crizotinib is not only used for the treatment of ALK- or ROS1-positive metastatic non-small cell lung cancer (NSCLC), but also for the treatment of adult and paediatric patients 1 year of age and older with unresectable, relapsed or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive interstitial myofibroblastic tumours (IMT). In addition, crizotinib has preclinical efficacy in the Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) patient cells, JAK2 mutant cell lines, and JAK2 mutant mouse models. Crizotinib is recommended for the treatment of patients with MPN, particularly in the setting of JAK inhibitor resistance[1].

XALKORI(R) (crizotinib)

Chemical Properties

Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.

Originator

Pfizer (United States)

Uses

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. In August 2011, the United States FDA approved crizotinib for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC).

Indications

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.

Definition

ChEBI: Crizotinib is 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 with locally advanced or metastatic non-small cell lung cancer (NSCLC) It has a role as an antineoplastic agent, a biomarker and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is an enantiomer of an ent-crizotinib.

brand name

Xalkori

General Description

Class: receptor tyrosine kinase; Treatment: NSCLC; Oral bioavailability = 43%; Elimination half-life = 42 h; Protein binding = 90%

Biochem/physiol Actions

Crizotinib (PF-02341066) is an ATP-competitive inhibitor of the receptor tyrosine kinases (RTKs) c-Met (hepatocyte growth factor receptor) and anaplastic lymphoma kinase (ALK). Crizotinib is a highly specific inhibitor of c-Met and ALK among > 120 different RTKs surveyed. Crizotinib was approved for treatment of a subtype of nonsmall-cell lung cancer (NSCLC) with ALK fusion mutations.

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.

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.
http://www.rxlist.com/xalkori-side-effects-drug-center.htm

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.

Synthesis_877399-52-5


Mesylation of tert-butyl-4-hydroxypiperidine-1-carboxylate (116) followed by displacement with 4-iodopyarazole (117) provided iodopyrazine 118 in 50¨C60% 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¨C80% 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¨C85% 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¨C85% 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¨C80% yield, which upon acid-promoted removal of the Boc protecting group and crystallization from CH3CN/H2O produced crizotinib (X) in 75¨C80% yield.

target

Primary targets: ALK/ROS1/MET

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: use alfentanil and fentanyl with caution. Antibacterials: concentration reduced by rifabutin and rifampicin - avoid; concentration increased by clarithromycin and telithromycin - avoid.
Antidepressants: St John’s wort may reduce concentration of crizotinib - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid.
Antifungals: concentration increased by ketoconazole and possibly with itraconazole and voriconazole - avoid.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide.
Antivirals: concentration possibly increased by atazanavir, indinavir, ritonavir and saquinavir - avoid.
Anxiolytics and hypnotics: increases concentration of midazolam.
Ciclosporin: use with caution.
Cytotoxics: possibly increases ibrutinib concentration - reduce dose of ibrutinib.
Ergot alkaloids: use with caution.
Grapefruit juice: may increase concentration of crizotinib, avoid.
Oestrogens and progestogens: contraceptive effect possibly reduced - avoid.
Sirolimus: use with caution.
Tacrolimus: use with caution.

Metabolism

Mainly metabolised in the liver by CYP3A4/5. The main metabolic pathways are oxidation (to crizotinib lactam) and O-dealkylation.
Excreted 53% via faeces (53% unchanged) and 22% via urine (2% unchanged).

storage

Store at +4°C

Mode 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876666/

References

[1] GURSKA L M, OKABE R, SCHURER A, et al. Crizotinib has Preclinical Efficacy in Philadelphia-negative Myeloproliferative Neoplasms.[J]. Clinical cancer research?: an official journal of the American Association for Cancer Research, 2022. DOI:10.1158/1078-0432.ccr-22-1763.

References

[1] zou hy1, li q, lee jh, arango me, mcdonnell sr, yamazaki s, koudriakova tb, alton g, cui jj, kung pp, nambu md, los g, bender sl,mroczkowski b, christensen jg. an orally available small-molecule inhibitor of c-met, pf-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. cancer res. 2007 may 1;67(9):4408-17.

Crizotinib Preparation Products And Raw materials

Global( 551)Suppliers
Supplier Tel Email Country ProdList Advantage
Shijiazhuang Dingmin Pharmaceutical Sciences Co., Ltd.
+86-0311-67591193 +8613931880626 sales02@dingminpharma.com China 252 58
Wuhan Golt Biotech Co., Ltd.
+8615389281203 maria@goltbiotech.com China 970 58
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+8615903659408 admin@ahdchem.com China 286 58
Zison Pharmaceutical (Shandong) Co., Ltd.
+86-0086-531-88259693 +86-18660188356 tracy.li@zisonpharm.com China 78 58
Hefei TianRui Pharmaceutical Chemical Co., Ltd.
+86-0551-68665055 +86-+86-18616906106 sales@trywchem.com China 148 58
Jinan Million Pharmaceutical Co., Ltd
0531-68659554 +8613031714605 info@millionpharm.com China 252 58
Henan Fengda Chemical Co., Ltd
+86-371-86557731 +86-13613820652 info@fdachem.com China 20284 58
BEIJING SJAR TECHNOLOGY DEVELOPMENT CO., LTD.
+86-18600796368 +86-18600796368 sales@sjar-tech.com China 456 58
Fuzhou Lista Biotechnology Co.,Ltd
sallychris2021@gmail.com China 75 58
Cangzhou Kangrui Pharma Tech Co. Ltd.,
+86-18632776803 +86-13833998158 cangzhoukangrui@126.com China 738 58

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View Lastest Price from Crizotinib manufacturers

Image Update time Product Price Min. Order Purity Supply Ability Manufacturer
Crizotinib pictures 2024-12-23 Crizotinib
877399-52-5
US $0.00-0.00 / kg 1kg >99% by HPLC 10kg/month Zison Pharmaceutical (Shandong) Co., Ltd.
Crizotinib pictures 2024-12-23 Crizotinib
877399-52-5
US $1.00-0.50 / kg 1kg 99% 200kg Jinan Million Pharmaceutical Co., Ltd
Crizotinib pictures 2024-12-19 Crizotinib
877399-52-5
US $0.00-0.00 / g 100g 99% 20kgs Cangzhou Kangrui Pharma Tech Co. Ltd.,
  • Crizotinib pictures
  • Crizotinib
    877399-52-5
  • US $0.00-0.00 / kg
  • >99% by HPLC
  • Zison Pharmaceutical (Shandong) Co., Ltd.
  • Crizotinib pictures
  • Crizotinib
    877399-52-5
  • US $1.00-0.50 / kg
  • 99%
  • Jinan Million Pharmaceutical Co., Ltd
  • Crizotinib pictures
  • Crizotinib
    877399-52-5
  • US $0.00-0.00 / g
  • 99%
  • Cangzhou Kangrui Pharma Tech Co. Ltd.,

Crizotinib Spectrum

(R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H- pyrazol-4-yl)pyridin-2-ylaMine [3-[[(R)-1-(2,6-Dichloro-3- fluorophenyl)ethyl]oxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-yl]aMine 2-PyridinaMine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]- Crozotinib Crizotinib,PF-02341066 Crizotinib (PF2341066) PF-02341066 Crizotinib 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine k-ras(g12c) inhibitor 6 NA Crizotinib Crizotinib, >=98% 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-2-pyridin 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-2-Pyridinamine (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]pyridin-2-amine Crizotinib PF 2341066 PF-02341066 PF-2341066/Crizotinib 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine Crizotinib Xalkori 3-[(1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY]-5-[1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL]PYRIDIN-2-AMINE 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine (R)-Crizotinib PF 2341066; PF2341066 CS-164 PF 02341066 - Crizotinib | PF 2341066 Crizotinib ? ?3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine Crizotinib USP/EP/BP Crizotinib DISCONTINUED 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4... CrizotinibQ: What is Crizotinib Q: What is the CAS Number of Crizotinib Q: What is the storage condition of Crizotinib Q: What are the applications of Crizotinib 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-2-aMinopyridine Xalkori Crizotini Crizotanib 877399-52-5 877395-52-5 87399-52-5 77399-52-5 877399-52-6 877388-52-5 C21H22Cl2FN5O Inhibitor Aromatic Chiral Reagents Heterocycles Inhibitors Intermediates & Fine Chemicals Pfizer Compounds Pharmaceuticals Anti-cancer & immunity API API chemical