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877399-52-5

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  • High quality 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine with best price and good quality cas:877399-52-5

    Cas No: 877399-52-5

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877399-52-5 Usage

Description

Crizotinib, marketed under the brand name Xalkori, is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer (NSCLC). It is a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK), both of which are important targets for cancer chemotherapy. Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation), and its solubility in aqueous media decreases over the range pH 1.6 to pH 8.2.
Used in Pharmaceutical Industry:
Crizotinib is used as an antineoplastic agent for the treatment of patients with locally advanced or metastatic 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 a potential antitumor agent that inhibits tumor cell growth by targeting specific kinases involved in cancer development and progression.
In August 2011, the United States FDA approved crizotinib for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). It is not known if XALKORI (crizotinib) is safe and effective in children.

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.

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 50–60% 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.

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).

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] 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.

Check Digit Verification of cas no

The CAS Registry Mumber 877399-52-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,7,7,3,9 and 9 respectively; the second part has 2 digits, 5 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 877399-52:
(8*8)+(7*7)+(6*7)+(5*3)+(4*9)+(3*9)+(2*5)+(1*2)=245
245 % 10 = 5
So 877399-52-5 is a valid CAS Registry Number.
InChI:InChI=1/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

877399-52-5 Well-known Company Product Price

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  • (PZ0191)  Crizotinib  ≥98% (HPLC)

  • 877399-52-5

  • PZ0191-5MG

  • 1,099.80CNY

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877399-52-5SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name Crizotinib

1.2 Other means of identification

Product number -
Other names (R)-Crizotinib

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

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More Details:877399-52-5 SDS

877399-52-5Downstream Products

877399-52-5Relevant articles and documents

Novel crizotinib–gnrh conjugates revealed the significance of lysosomal trapping in gnRH-based drug delivery systems

Murányi, József,Varga, Attila,Gyulavári, Pál,Pénzes, Kinga,Németh, Csilla E.,Csala, Miklós,Peth?, Lilla,Csámpai, Antal,Halmos, Gábor,Peták, István,Vályi-Nagy, István

, (2019)

Several promising anti-cancer drug–GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)-or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [D-Lys6]–GnRH-I targeting peptide. Our most prominent crizotinib–GnRH conjugates, the amide-bond-containing [D-Lys6(crizotinib*)]–GnRH-I and the ester-bond-containing [D-Lys6(MJ55*)]–GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib–GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets—the ATP-binding site of RTKs— and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib–GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug–GnRH conjugates.

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

Chen, Jianli,Cheng, Pengfei,Su, Weike,Xie, Xiaoxuan,Xu, Feng,Yu, Zhiqun

supporting information, p. 2252 - 2259 (2020/11/26)

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.

Synthesis method of anti-tumor drug crizotinib

-

, (2018/09/08)

The invention relates to a synthesis method of an anti-tumor drug crizotinib. 3-hydroxy-2-aminopyridine is used as a raw material; amino is firstly protected; afterwards, a Mitsunobu reaction, the bromination deprotection and the Suzuki coupling are carried out; finally, the deprotection is carried out to prepare and obtain the crizotinib. According to the method, in the condition that a step is not added, the protection on two nitrogen atoms are simultaneously removed to obtain the crizotinib; the route is used for avoiding the previous scheme that the nitrification is firstly carried out andthen the reduction is carried out; much waste acid and wastewater which are generated by the nitrification of concentrated acid are avoided; meanwhile, the environmental pollution brought by the reduction of iron powder or the high cost of catalytic hydrogenation reduction and the high requirement of a device, are also avoided; when the Suzuki coupling is carried out in the condition that the amino is protected, the strong electron donating effect of the para-position amino of pyridine bromide is avoided; the reaction activity of the bromide is increased; the yield of a Suzuki reaction is also improved, and the method has a series of advantages of being few in step, short in cycle, cheap and easily obtained in raw material, low in cost, lower in requirement on the device, high in processstability, green and environmentally friendly, and the like.

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