Encorafenib (LGX818)

Base Information

• Chemical Name: Encorafenib (LGX818)
• CAS No.: 1269440-17-6
• Molecular Formula: C22H27ClFN7O4S
• Molecular Weight: 540.018
• Mol file: 1269440-17-6.mol

Synonyms:LGX 818;LGX818;LGX-818;(S)-Methyl [1-[[4-[3-[5-chloro-2-fluoro-3-(methylsulfonamido)phenyl]-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate

Chemical Property of Encorafenib (LGX818)

Chemical Property:

• PKA: 5.94±0.10(Predicted)
• PSA: 152.00000
• Density: 1.45±0.1 g/cm3(Predicted)
• LogP: 5.33960
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility.: DMSO (Slightly), Methanol (Slightly)

Purity/Quality:

99% ^*data from raw suppliers

LGX 818 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Encorafenib (LGX818) is a new-generation BRAF inhibitor that is under evaluation in clinical trials. However, the underlying mechanism remains to be elucidated. Here we show that LGX818 potently decreased ERK phosphorylation and inhibited proliferation in BRAFV600E melanoma cell lines. Moreover, LGX818 downregulated CyclinD1 in a glycogen synthase kinase 3β-independent manner and induced cell cycle arrest in the G1 phase.
• Uses: LGX 818 is potent and selective BRAFV600E kinase inhibitor and can be used for the treatment of proliferative diseases such as solid tumor diseases.
• Clinical Use: Encorafenib (LGX818) is a new-generation BRAF inhibitor. It is currently under investigation in clinical trials for the treatment of BRAF mutant metastatic melanoma patients . LGX818 induces sustained mitogen-activated protein kinase (MAPK) pathway inhibition and has selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E. However, the mechanism by which LGX818 suppresses BRAF mutant melanoma cell proliferation has not been thoroughly investigated.

Technology Process of Encorafenib (LGX818)

There total 17 articles about Encorafenib (LGX818) 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:

(S)-methyl 1-(4-(3-(5-chloro-2-fluoro-3-(N-(methylsulfonyl)methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (1269440-99-4) → methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate (1269440-17-6)

Guidance literature:

(S)-methyl 1-(4-(3-(5-chloro-2-fluoro-3-(N-(methylsulfonyl)methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; With sodium hydroxide; In 2-methyltetrahydrofuran; water; at 20 - 23 ℃; for 0.5h;

With hydrogenchloride; In 2-methyltetrahydrofuran; water; pH=6 - 6.5;

With sodium hydrogencarbonate; In 2-methyltetrahydrofuran; water; pH=8.5;

Reference yield:

(S)-methyl 1-(4-(3-(3-amino-2-chloro-5-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (1269440-76-7) + methanesulfonyl chloride (124-63-0) → methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate (1269440-17-6)

Guidance literature:

With pyridine; In dichloromethane; at 20 ℃; for 16h;

Reference yield:

2-bromo-4-chloro-1-fluorobenzene (1996-30-1) → methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate (1269440-17-6)

Guidance literature:

Multi-step reaction with 7 steps

1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C

1.2: -78 - 20 °C

2.1: diphenylphosphoranyl azide; triethylamine / toluene / 2 h / 75 - 84 °C

2.2: 0.25 h / 35 °C

3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 100 °C

4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol; water; toluene / 16 h / 80 °C

5.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C

6.1: triethylamine / 2-methyltetrahydrofuran / -5 - 20 °C

6.2: pH 6 - 6.5

6.3: 0.17 h / 20 °C / pH 7 - 7.5

7.1: sodium hydroxide / 2-methyltetrahydrofuran; water / 0.5 h / 20 - 23 °C

7.2: pH 6 - 6.5

7.3: pH 8.5

With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; diphenylphosphoranyl azide; potassium acetate; sodium carbonate; triethylamine; trifluoroacetic acid; sodium hydroxide; lithium diisopropyl amide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; In tetrahydrofuran; 2-methyltetrahydrofuran; 1,4-dioxane; ethanol; dichloromethane; water; toluene;

upstream raw materials:

(S)-methyl 1-(4-(3-(3-amino-2-chloro-5-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

methanesulfonyl chloride

2-bromo-4-chloro-1-fluorobenzene

3-bromo-5-chloro-2-fluorobenzoic acid

Refernces