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%, ^*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:

• General Description: Ceritinib (LDK378) is an ALK inhibitor used to treat non-small cell lung cancer (NSCLC), particularly in cases involving crizotinib-resistant mutations. Research has shown that modifying ceritinib by replacing its terminal piperidine with aliphatic amines can enhance its efficacy against resistant mutants, including the highly refractory G1202R mutation. One such derivative, compound 10 (KRCA-764), demonstrated potent activity (IC50 = 1.8 nM) against resistant ALK variants and improved pharmacokinetic properties compared to ceritinib, suggesting potential for further development as a next-generation ALK inhibitor.

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

Refernces

Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R

10.1016/j.ejmech.2016.11.046

The research explores the development of new ALK inhibitors to address resistance issues in non-small cell lung cancer (NSCLC) patients. The study focuses on modifying ceritinib by replacing its piperidine fragment with diverse aliphatic amines to improve its efficacy against crizotinib-resistant mutants, particularly the highly resistant G1202R mutant. The researchers synthesized and evaluated a series of compounds, with compound 10 (KRCA-764) showing promising activities against both wild-type ALK and crizotinib-resistant mutants, including G1202R, with an IC50 of 1.8 nM. This compound also exhibited better pharmacokinetic profiles than ceritinib. Key chemicals involved in the synthesis included 4-methyl-2-nitroanisole, phenylthioacetonitrile, sodium hydroxide, Pd/C, and various amines. The study utilized enzymatic and cell-based assays to evaluate the inhibitory activities of the synthesized compounds, and molecular docking studies were performed to understand the binding modes. In vivo xenograft studies in mice demonstrated that compound 10 had similar potency to ceritinib, suggesting further optimization could lead to clinical candidates capable of overcoming ALK mutant resistance.