1195768-06-9

Basic information

• Product Name: Dabrafenib Mesylate(GSK-2118436B)
• Synonyms: Dabrafenib Mesylate(GSK-2118436B);Dabrafenib Mesylate;GSK 2118436 Mesylate;GSK 2118436B;GSK2118436 Mesylate;GSK-2118436 Mesylate;Dabrafenib Mesylate (API);GSK 2118436 methanesulfonate salt
• CAS NO: 1195768-06-9
• Molecular Formula: CH₄O₃S*C₂₃H₂₀F₃N₅O₂S₂
• Molecular Weight: 615.6680696
• EINECS: 1592732-453-0
• Product Categories: Raf B protein kinase inhibitor
• Mol File: 1195768-06-9.mol
• Article Data: 6

Chemical Properties

• Appearance: /
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly)
• Stability: Hygroscopic
• CAS DataBase Reference: Dabrafenib Mesylate(GSK-2118436B)(CAS DataBase Reference)
• NIST Chemistry Reference: Dabrafenib Mesylate(GSK-2118436B)(1195768-06-9)
• EPA Substance Registry System: Dabrafenib Mesylate(GSK-2118436B)(1195768-06-9)

Safety Data

• Hazardous Substances Data: 1195768-06-9(Hazardous Substances Data)

Usage

Description

Dabrafenib Mesylate (GSK-2118436B) is a methanesulfonate salt derived from Dabrafenib, a selective ATP-competitive inhibitor of certain mutated forms of BRAF kinase, which are associated with stimulating tumor growth, such as the BRAF V600E mutation. Dabrafenib Mesylate is used to inhibit BRAF V600-mutation positive cancer cell growth, both in vitro and in vivo, and has been approved by the U.S. FDA for the treatment of metastatic BRAF-mutant melanoma.

Uses

Used in Pharmaceutical Industry:
Dabrafenib Mesylate (GSK-2118436B) is used as an anticancer agent for the treatment of metastatic BRAF-mutant melanoma. It works by reversibly inhibiting the BRAF(V600E) mutant kinase, leading to tumor regression and improved patient outcomes.
Used in Research and Development:
Dabrafenib Mesylate (GSK-2118436B) is used as a research tool for studying the role of BRAF kinase mutations in cancer cell growth and the development of targeted therapies for various types of cancer.

Synthesis

Commercially available fluoroaniline 40 was first converted to sulfonamide 42 in 91% yield by treatment with 2,5-difluorobenzenesulfonyl chloride (41) in the presence of pyridine. Next, deprotonation of 2-chloro-4-methylpyrimidine (43) with lithium bis(trimethylsilyl)amide (LHMDS) followed by addition to ester 42 afforded chloropyrimidine 44 in 72% yield. Bromination followed by thiazole formation through the use of 2,2-dimethylpropanethioamide gave the penultimate target 45 in 80% over two steps. Chloropyrimidine 45 was subjected to SNAr conditions with ammonium hydroxide to furnish the aminopyrimidine in 88% yield, and this was followed by exposure to methanesulfonic acid to afford dabrafenib mesylate (VI) in 85% yield.

references

[1]namba h, nakashima m, hayashi t, hayashida n, maeda s, rogounovitch ti, ohtsuru a, saenko va, kanematsu t, yamashita s. clinical implication of hot spot braf mutation, v599e, in papillary thyroid cancers. j. clin. endocrinol. metab. 2003; 88 (9): 4393–7. [2]tan yh, liu y, eu kw, ang pw, li wq, salto-tellez m, iacopetta b, soong r. detection of braf v600e mutation by pyrosequencing. pathology 2008; 40 (3): 295–8.[3]davies h, bignell gr, cox c, et al. mutations of the braf gene in human cancer. nature. 2002; 417: 949-954.[4]ma xh, piao sf, dey s, mcafee q, karakousis g, villanueva j, hart ls, levi s, hu j, zhang g, lazova r, klump v, pawelek jm, xu x, xu w, schuchter lm, davies ma, herlyn m, winkler j, koumenis c, amaravadi rk. targeting er stress-induced autophagy overcomes braf inhibitor resistance in melanoma. j clin invest. 2014; 124(3): 1406-17.

Upstream product

• 75-75-2 methanesulfonic acid 
• 1195765-45-7 dabrafenib 
• 60230-36-6 2,6-difluorobenzene-1-sulfonyl chloride 
• 1195768-20-7 N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide 
• 1195768-18-3 3-amino-2-fluorobenzoic acid methyl ester 
• 1195768-19-4 3-(2,6-difluorobenzenesulfonamido)-2-fluorobenzoic acid methyl ester 
• 1195768-23-0 N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide 

Relevant articles and documents

PHARMACEUTICAL COMBINATION COMPRISING THE PI3K INHIBITOR ALPELISIB AND THE B-RAF INHIBITOR DABRAFENIB; THE USE OF SUCH COMBINATION IN THE TREATMENT OR PREVENTION OF CANCER

The present disclosure pertains to a pharmaceutical combination comprising (a) alpha- isoform specific PI3K inhibitor and (b) a B-RAF inhibitor; combined preparations and pharmaceutical compositions thereof; the uses of such combination in the treatment or prevention of cancer; and methods of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of such combination.

Novel Crystal Form of Dabrafenib Mesylate and Preparation Method Thereof

Disclosed are a novel crystal form of Dabrafenib mesylate and preparation method thereof. The novel crystal form of the present invention is more stable in water or an aqueous system, and has greater solubility and dissolution in water, thus having better stability and bioavailability compared with the existing crystal forms.

COMBINATIONS OF AN ANTI-PD-L1 ANTIBODY AND A MEK INHIBITOR AND/OR A BRAF INHIBITOR

A novel combination comprising the MEK inhibitor N-{3-[3-cyclopropyl-5-(2-fluoro- 4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3- d]pyrimidin-1 -yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, and/or a B-Raf inhibitor, particularly N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1 - dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody; pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf and/or neutralizing or inhibiting the interaction between PD-L1 and its receptor, e.g. PD-1, is beneficial, eg. cancer.