ChemicalBook > CAS DataBase List > Crizotinib

Crizotinib

Product Name
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
Formula Weight
450.34
MOL File
877399-52-5.mol
More
Less

Crizotinib Property

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)
form 
powder
pka
9.81±0.10(Predicted)
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.
InChI
InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
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
More
Less

Safety

Safety Statements 
24/25
RIDADR 
UN 3077 9 / PGIII
WGK Germany 
3
HazardClass 
IRRITANT
HS Code 
29333990
More
Less

Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H317May cause an allergic skin reaction

H319Causes serious eye irritation

H341Suspected of causing genetic defects

H400Very toxic to aquatic life

Precautionary statements

P201Obtain special instructions before use.

P273Avoid release to the environment.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P308+P313IF exposed or concerned: Get medical advice/attention.

More
Less

N-Bromosuccinimide Price

Sigma-Aldrich
Product number
PZ0191
Product name
Crizotinib
Purity
≥98% (HPLC)
Packaging
5MG
Price
$132
Updated
2024/03/01
Cayman Chemical
Product number
12087
Product name
Crizotinib
Purity
≥98%
Packaging
5mg
Price
$114
Updated
2023/06/20
Cayman Chemical
Product number
12087
Product name
Crizotinib
Purity
≥98%
Packaging
10mg
Price
$197
Updated
2023/06/20
Cayman Chemical
Product number
12087
Product name
Crizotinib
Purity
≥98%
Packaging
50mg
Price
$87
Updated
2024/03/01
Tocris
Product number
4368
Product name
Crizotinib
Purity
≥99%(HPLC)
Packaging
10
Price
$281
Updated
2021/12/16
More
Less

Crizotinib Chemical Properties,Usage,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].



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).

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.

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.

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.


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

Raw materials

Preparation Products

More
Less

Crizotinib Suppliers

Hubei Dibai Chemical Co., Ltd.
Tel
027-87058617 15872383390
Fax
027-87058617
Email
hbdibo@163.com
Country
China
ProdList
885
Advantage
58
Guangzhou Zhiya Chemdrugs Co.,Ltd
Tel
18122150900
Fax
QQ:2869377561
Email
sculk28@163.com
Country
China
ProdList
646
Advantage
55
Hangzhou Chemtrue Bio-Tech Co.,Ltd.
Tel
0571-86828652 18857119830
Fax
0571-83522824
Email
sales@chemtrue-bio.com
Country
China
ProdList
326
Advantage
58
Tai Zhou World Pharm & Chem Co., Ltd
Tel
0576-85301198 13736201658
Email
16029347@qq.com
Country
China
ProdList
104
Advantage
58
Jinan XinKe Pharmaceutical Technology Co., Ltd.
Tel
0531-88259693 17854196142
Fax
0531-88259693
Email
2820602043@qq.com
Country
China
ProdList
100
Advantage
58
Shijiazhuang Dingmin pharmaceutical Sciences Co.,Ltd
Tel
+86-0311-67591193 +86-15030197620
Fax
QQ:2786999724
Email
sales02@dingminpharma.com
Country
China
ProdList
300
Advantage
58
Shanghai Boyle Chemical Co., Ltd.
Tel
Fax
86-21-57758967
Email
sales@boylechem.com
Country
China
ProdList
2922
Advantage
55
J & K SCIENTIFIC LTD.
Tel
010-82848833 400-666-7788
Fax
86-10-82849933
Email
jkinfo@jkchemical.com
Country
China
ProdList
96815
Advantage
76
Chembest Research Laboratories Limited
Tel
+86-21-20908456
Fax
021-58180499
Email
sales@BioChemBest.com
Country
China
ProdList
6005
Advantage
61
Beijing HwrkChemical Technology Co., Ltd
Tel
010-89508211 18501085097
Fax
010-89508210
Email
sales.bj@hwrkchemical.com
Country
China
ProdList
8418
Advantage
55
More
Less

View Lastest Price from Crizotinib manufacturers

Zison Pharmaceutical (Shandong) Co., Ltd.
Product
Crizotinib 877399-52-5
Price
US $0.00-0.00/kg
Min. Order
1kg
Purity
>99% by HPLC
Supply Ability
10kg/month
Release date
2023-01-06
Jinan Million Pharmaceutical Co., Ltd
Product
Crizotinib 877399-52-5
Price
US $1.00-0.50/kg
Min. Order
1kg
Purity
99%
Supply Ability
200kg
Release date
2023-12-11
Cangzhou Kangrui Pharma Tech Co. Ltd.,
Product
Crizotinib 877399-52-5
Price
US $0.00-0.00/g
Min. Order
100g
Purity
99%
Supply Ability
20kgs
Release date
2024-12-02

877399-52-5, CrizotinibRelated Search:


  • 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-2-aMinopyridine
  • (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
  • Xalkori
  • 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 (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
  • Crizotini
  • 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
  • Crizotanib
  • 877399-52-5
  • 877395-52-5
  • 87399-52-5
  • 77399-52-5
  • 877399-52-6
  • 877388-52-5
  • C21H22Cl2FN5O
  • API
  • API
  • Inhibitor
  • Aromatic
  • Chiral Reagents
  • Heterocycles
  • Inhibitors
  • Intermediates & Fine Chemicals
  • Pfizer Compounds
  • Pharmaceuticals
  • Anti-cancer & immunity
  • chemical