918504-65-1

Basic information

• Product Name: N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide
• Synonyms: N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide;PLX4032 (VeMurafenib);R7204;N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaM;PLX4032, R7204, RG7204, RO5185426;VeMurafenib (PLX4032, RG7204);N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide Vemurafenib PLX 4032;Zelboraf (vemurafenib)
• CAS NO: 918504-65-1
• Molecular Formula: C23H18ClF2N3O3S
• Molecular Weight: 489.9221264
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Protein Kinase Inhibitors and Activators;Sulfur & Selenium Compounds;API;Inhibitor;RG7204;Antineoplastic;Inhibitors;MAPK
• Mol File: 918504-65-1.mol

Chemical Properties

• Appearance: /
• Density: 1.46
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to 100 mg/ml)
• PKA: 6.26±0.10(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide(CAS DataBase Reference)
• NIST Chemistry Reference: N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide(918504-65-1)
• EPA Substance Registry System: N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide(918504-65-1)

Safety Data

• Hazardous Substances Data: 918504-65-1(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide is used as an antitumor agent for the treatment of patients with metastatic melanoma with the BRAFV600E mutation. It works by inhibiting the proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAFV600E or other mutant BRAF proteins altered at codon 600.
Used in Pharmaceutical Industry:
N-(3-(5-(4-Chlorophenyl)-1H-pyrrolo[2,3-B]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonaMide is used as a potent inhibitor of B-RafV600E kinase (IC50=13 nM) compared to its potency against wildtype B-raf (IC50=160 nM). It is fairly selective versus a panel of 200 kinases and has been approved by the United States FDA in August 2011 for the treatment of patients with metastatic melanoma with the BRAFV600E mutation.

Originator

Plexxikon (United States)

Biological Activity

Vemurafenib (PLX4032, RG7204, RO5185426) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM in cell-free assay. 10-fold selective for B-RafV600E over wild-type B-Raf in enzymatic assays and the cellular selectivity can exceed 100-fold. Vemurafenib (PLX4032, RG7204) induces autophagy.

in vitro

PLX4032 inhibits B-RAFV600E, C-RAF, as well as wildtype B-RAF, with IC50 of 31 nM, 48 nM and 100 nM, respectively. PLX4032 also inhibits several non-RAF kinases, including ACK1, KHS1, and SRMS, with IC50 of 18 nM to 51 nM. In melanoma cell lines, the inhibitory effect by PLX4032 depends on B-RAF mutational status, because PLX4032 potently inhibits those harboring B-RAF V600 mutants, including V600E, V600D, V600K, and V600R, but not wildtype or other mutants. The IC50 values of PLX4032 on these cells, including MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058, ranges from 20 nM to 1 μM. In these cells, PLX4032 (0.1 μM to 30 μM) also inhibits the phosphorylation of both MEK1/2 and ERK1/2. PLX4032 is highly effective in the treatment of melanoma, for its ability of inhibiting B-RAFV600E. However, PLX4032 displays limited effect in colon cancer patients that also carrying B-RAFV600E oncoprotein. The reason for this is that, in colon cancer cells, B-RAFV600E inhibition by PLX4032 results in a rapid feedback EGFR activation, which compensates for the PLX4032-inhibited cell proliferation.

in vivo

In B-RAFV600E-mutant mice xenograft models, PLX4032 (6 mg/kg–20 mg/kg) inhibits tumor growth. In mice xenograft models of LOX, Colo829, and A375 cells, PLX4032 (12.5 mg/kg–100 mg/kg) inhibits tumor growth and prolongs mice survival.

References

1) Khazak?et al. (2007),?Selective Raf inhibition in cancer therapy; Expert Opin. Ther. Targets,?11?1587 2) Tap?et al.?(2010),?Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma; Neoplasia,?12?637 3) Lee?et al.?(2010),?PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas; Pigment Cell Melanoma Res.,?23?820 4) Flaherty?et al.?(2010),?Inhibition of mutated, activated BRAF in metastatic melanoma; N. Engl. J. Med.,?363?809

Upstream product

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Downstream Products

• 1577225-39-8 (S)-2-amino-N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-methyl-N-(propylsulfonyl)butanamide hydrochloride 
• 1567347-33-4 1-(5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl dihydrogen phosphate 

Relevant articles and documents

Simple preparation method of vemurafenib and analogues thereof

The invention provides a simple preparation method of vemurafenib and analogues thereof. The method includes: subjecting para-substituted phenylacetaldehyde II and N-[2, 4-disubstituted-3-(cyanopropionyl)phenyl]n-propanesulfonamide III to azeotropic dewatering and condensation reaction under alkaili catalysis, condensing the obtained condensation product and the methylenation reagent V(N, N-dimethylformamide or tri-orthoformate), and then performing cyclization with ammonia to obtain vemurafenib or analogues thereof. The method for preparation of vemurafenib provided by the invention has the characteristics of low cost, mild process conditions, low operation requirements, short reaction time, high production efficiency, simple process operation, little waste water production, green and environmental protection, high yield and purity, and is beneficial to green industrial production of vemurafenib. At the same time, the method provided by the invention can prepare vemurafenib analogues,and is of important significance for the drug efficacy study of similar compounds.

NEW PROCESSES FOR THE PREPARATION OF VEMURAFENIB

The present invention relates to novel processes for the manufacture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (I), wherein no protection-deprotection sequences or halogenation steps are required and the use of palladium catalysts is minimized. Formula (I)

SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS

The present invention relates to a process for the preparation substantially pure propane-1-sulfonicacid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib of Formula (I). The present invention further relates to a process for the preparation substantially pure propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII)

SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS

The present Invention relates to a process for the preparation substantially pure propane- 1 -sulfonicacid- { 3 -[5 -(4-chiorophenyI)-1 H-pyrrolo [2,3-b]pyridine-3 -carbonyl]-2,4-difluoro-phenyl} -amide or Vemurafenib of Formula (1), The present invention further relates to a process for the preparation substantially pure propane- 1 -sulfonic acid- { 3 - [5-(4-chlorophenyi)-1H-pyrrolo [2,3-b]pyridine-3 -carbonyl] -2,4-difluoro-phenyl} -amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII).

NOVEL PROCESSES FOR THE PREPARATION OF VEMURAFENIB

The present invention provides novel intermediates of vemurafenib or a pharmaceutically acceptable salt thereof and processes for its preparation. The present invention also provides novel processes for preparation of vemurafenib or a pharmaceutically acceptable salt thereof using the novel intermediates.

CRYSTALLINE FORMS OF VEMURAFENIB

The invention relates to new crystalline forms of vemurafenib, i.e. N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide of formula (I), exhibiting the following characteristic reflections in the X-ray powder pattern, measured with the use of CuKa radiation at the wavelength λ = 0.1542 nm: 6.5; 9.7; 18.0; 19.5 and 23,7 ± 0.2° 2-theta, and a method for the preparation thereof.

SOLID STATE FORMS OF VEMURAFENIB HYDROCHLORIDE

Provided herein are solid state forms of Vemurafenib hydrochloride, processes for preparing the solid state forms, as well as pharmaceutical compositions and formulations comprising said solid state forms.

SYNTHESIS OF PYRROLO [2, 3 - B] PYRIDINES

Provided herein are intermediates and processes useful for facile synthesis of biologically active molecules.

Rapid, microwave-assisted organic synthesis of selective V600EBRAF inhibitors for preclinical cancer research

We report dramatically improved total syntheses of two highly selective V600EBRAF inhibitors, PLX4720 and PLX4032, that leverages microwave-assisted organic synthesis (MAOS). Compared with previously reported approaches, our novel MAOS method significantly reduces overall reaction time without compromising yield. In addition to providing a gram-scale route to these compounds for preclinical oncology research, we anticipate this approach could accelerate the synthesis of azaindoles in high-throughput, library-based formats.

Novel Processes for the manufacture of Propane-1-sulfonic acid -amide

According to the present invention there are provided novel processes for the manufacture of the compound of formula 1 as well as intermediates and novel synthesis routes for key intermediates used in those processes.