Crizotinib

Base Information

• Chemical Name: Crizotinib
• CAS No.: 877399-52-5
• Molecular Formula: C₂₁H₂₂Cl₂FN₅O
• Molecular Weight: 450.343
• Hs Code.: 29333990
• Mol file: 877399-52-5.mol

Synonyms:PF-02341066;[3-[[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]oxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-yl]amine;3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine;2-Pyridinamine,3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-;

Chemical Property of Crizotinib

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 192 °C
• Refractive Index: 1.673
• Boiling Point: 599.177 °C at 760 mmHg
• PKA: 9.81±0.10(Predicted)
• Flash Point: 316.171 °C
• PSA: 77.99000
• Density: 1.475 g/cm³
• LogP: 5.94770
• 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)

Purity/Quality:

99% ^*data from raw suppliers

Crizotinib ≥99%(HPLC) ^*data from reagent suppliers

Safty Information:

• Safety Statements: 24/25

MSDS Files:

SDS file from LookChem

Useful:

• Description: Crizotinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. It 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. Altogether, this agent inhibits tumor cell growth.XALKORI?(crizotinib) is a prescription medicine used to treat people with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by a defect in either a gene called ALK (anaplastic lymphoma kinase) or a gene called ROS1. It is not known if XALKORI is safe and effective in children.
• 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.
• 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.
• 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.

Technology Process of Crizotinib

There total 64 articles about Crizotinib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.6%

C31H38Cl2FN5O5 (1569895-72-2) → crizotinib (877399-52-5)

Guidance literature:

With hydrogenchloride; In ethanol; dichloromethane; water; at 0 - 20 ℃; for 12h;

Reference yield: 98.0%

C36H46Cl2FN5O7 → crizotinib (877399-52-5)

Guidance literature:

With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20 ℃; for 12h; Solvent;

Reference yield: 97.8%

tert-butyl 4-(4-(6-((tert-butoxycarbonyl)amino)-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate → (+/-)-PF023401066 (877400-66-3,877399-52-5)

Guidance literature:

With hydrogenchloride; In ethanol; dichloromethane; water; at 20 ℃; for 12h; Reagent/catalyst; Solvent;

upstream raw materials:

4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

(S)‐1‐(2,6-dichloro-3-fluorophenyl)ethanol

5-bromo-3-[1 (R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine

tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Refernces

• 1、 -. "Purification method of crizotinib". Paragraph 0028-0039. . Retrieved 2020/07/15.
• 2、 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. "Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2". . p. 1507 - 1513. Retrieved 2019/04/17.