Ceritinib (LDK378)

Base Information

• Chemical Name: Ceritinib (LDK378)
• CAS No.: 1032900-25-6
• Molecular Formula: C28H36ClN5O3S
• Molecular Weight: 558.145
• Mol file: 1032900-25-6.mol

Synonyms:Ceritinib; LDK 378; 5-chloro-n4-(2-((1-methylethyl)sulfonyl)phenyl)-n2-(5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl)-2,4-pyrimidinediamine

Chemical Property of Ceritinib (LDK378)

Chemical Property:

• Boiling Point: 720.7±70.0 °C(Predicted)
• PKA: 10.16±0.10(Predicted)
• PSA: 116.85000
• Density: 1.251±0.06 g/cm3(Predicted)
• LogP: 7.26640
• Storage Temp.: -20°C Freezer
• Solubility.: Chloroform (Slightly), Methanol (Slightly)

Purity/Quality:

99%min., ^*data from raw suppliers

5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Ceritinib (previously LDK378l, brand name Zykadia; Novartis Pharmaceuticals) is an oral small molecule tyrosine kinase inhibitor of ALK [87]. Preclinical studies suggested that it would inhibit ROS1 as well [88, 89].
• Uses: 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine, is a Anaplastic lymphoma kinase (ALK) inhibitor.
• Indications: Ceritinib (Zykadia(R), Novartis), approved in 2014, was developed as a second-generation ALK inhibitor for patients with NSCLC who have developed crizotinib resistance. Ceritinib addresses two of the most common ALK mutants that lead to crizotinib resistance, L1196M andG1269A, but is ineffective for G1202R and F1174C variants of ALK.
• Clinical Use: ALK-inhibitor: Treatment of anaplastic lymphoma kinase (ALK)- positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib
• Drug interactions: Potentially hazardous interactions with other drugs Anti-arrhythmics: possibly increased risk of ventricular arrhythmias with amiodarone, disopyramide, dronedarone and flecainide. Antibacterials: possibly increased risk of ventricular arrhythmias with bedaquiline, clarithromycin, delamanid, IV erythromycin, moxifloxacin and telavancin; concentration reduced by rifampicin and possibly rifabutin - avoid. Antidepressants: risk of QT prolongation with citalopram, escitalopram, venlafaxine and tricyclics that prolong the QT interval - avoid; concentration possibly reduced by St John’s wort - avoid. Anti-emetics: possibly increased risk of ventricular arrhythmias with domperidone and ondansetron. Antiepileptics: possibly increased concentration with carbamazepine - avoid; concentration possibly reduced by fosphenytoin, phenobarbital, phenytoin and primidone. Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid or reduce ceritinib doseAntihistamines: avoid with hydralazine due to risk of QT prolongation. Antimalarials: possibly increased risk of ventricular arrhythmias with artemether and lumefantrine, piperaquine with artenimol, chloroquine and quinine - avoid. Antipsychotics: possibly increased risk of ventricular arrhythmias with droperidol and haloperidol; avoid with other antipsychotics that prolong the QT interval; increased risk of agranulocytosis with clozapine - avoid. Antivirals: concentration possibly increased by atazanavir, fosamprenavir, lopinavir, ritonavir, saquinavir and tipranavir - avoid or reduce dose; risk of QT prolongation with dasatinib - avoid. Apomorphine: risk of QT prolongation - avoid. Beta-blockers: possibly increased risk of ventricular arrhythmias with sotalol. Ciclosporin: may increase ciclosporin concentration - avoid. Cobicistat: concentration of ceritinib increased - avoid or adjust ceritinib dose. Cytotoxics: risk of QT prolongation with arsenic trioxide, bosutinib, cabozantib, crizotinib, eribulin, lapatinib, nilotinib, osimertinib, panobinostat, pazopanib, sorafenib, sunitinib, vandetanib, vemurafenib, vinflunine - avoid; concentration possibly increased by idelalisib - avoid or adjust ceritinib doseEnzalutamide: increases ceritinib concentration - avoid. Methadone: possibly increased risk of ventricular arrhythmias. Pasireotide: possibly increased risk of ventricular arrhythmias - avoid. Ranolazine: possibly increased risk of ventricular arrhythmias - avoid. Sirolimus: avoid concomitant use. Tacrolimus: avoid concomitant use. Tetrabenazine: possibly increased risk of ventricular arrhythmias - avoid. Tizanidine: possibly increased risk of ventricular arrhythmias - avoid. Warfarin - avoid concomitant use.

Technology Process of Ceritinib (LDK378)

There total 76 articles about Ceritinib (LDK378) 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: 97.9%

C35H40ClN5O3S → 5-chloro-N2-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine (1032900-25-6)

Guidance literature:

With palladium on activated charcoal; hydrogen; at 35 ℃; under 7500.75 Torr;

Reference yield: 93.0%

2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methyl-pyrimidin-4-amine (761440-16-8) + 5-chloro-N2-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride (1190399-91-7) → 5-chloro-N2-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine (1032900-25-6)

Guidance literature:

2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methyl-pyrimidin-4-amine; 5-chloro-N²-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N⁴-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride; In isopropyl alcohol; for 16h; Reflux; Large scale;

With sodium hydroxide; In ethanol; water; isopropyl alcohol; at 55 ℃; Large scale;

Reference yield: 92.6%

2-isopropylsulfonylchlorobenzene (70398-95-7) + C24H34ClN5O3 → 5-chloro-N2-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine (1032900-25-6)

Guidance literature:

2-isopropylsulfonylchlorobenzene; C₂₄H₃₄ClN₅O₃; With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium tert-butylate; In toluene; at 85 - 90 ℃; for 2h;

With hydrogenchloride; In ethanol; water; at 45 ℃; for 1h;

upstream raw materials:

5-chloro-N₂-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N₄-(2-(propane-2-sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride

2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methyl-pyrimidin-4-amine

4-(4-amino-5-isopropoxy-2-methylphenyl)-piperidine-1-carboxylic acid tert-butyl ester

4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)phenylamino]pyrimidin-2-ylamino}-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester

Downstream raw materials:

5-chloro-N₂-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N₄-(2-(propane-2-sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride

5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride

Refernces

• 1、 Liu, Haidong,Li, Yuan,Wang, Dongdong,Qin, Yu,Ji, Min. "An efficient synthesis of Ceritinib (LDK378) using a sandmeyer reaction". . p. 475 - 477. Retrieved 2015.
• 2、 -. "Chemical Process for Preparing Pyrimidine Derivatives and Intermediates Thereof". . . Retrieved 2020/02/20.
• 3、 -. "Diaminopyrimidine compound and application". Paragraph 0085-0089. . Retrieved 2020/03/13.