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| Dabrafenib Mesylate(GSK-2118436B) Basic information | | Description |
| Dabrafenib Mesylate(GSK-2118436B) Chemical Properties |
| Melting point | >234oC (dec.) | | storage temp. | Hygroscopic, -20°C Freezer, Under inert atmosphere | | solubility | DMSO (Slightly, Heated), Methanol (Slightly) | | form | White solid. | | color | White to Off-White | | Stability: | Hygroscopic |
| Dabrafenib Mesylate(GSK-2118436B) Usage And Synthesis |
| Description | Dabrafenib Mesylate is a salt form of Dabrafenib. Dabrafenib is an inhibitor of certain mutated forms of BRAF kinase, several of which may be associated with stimulating tumour growth (e.g. the BRAF V600E mutation), and Dabrafenib is also an inhibitor of BRAF V600-mutation positive cancer cell growth, both in vitro and in vivo.
| | Description | Dabrafenib mesylate, sold by GlaxoSmithKline under the trade
name Tafinlar, was approved by the U.S. FDA in May 2013 for
the treatment of metastatic BRAF-mutant melanoma. Dabrafenib
reversibly inhibits the BRAF(V600E) mutant kinase as a selective
ATP-competitive inhibitor which results in tumor regression. | | Uses | Dabrafenib is an inhibitor of mutated BRAF kinase and has clinical activity with a manageable safety profile in clinical trials of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. | | Definition | ChEBI: A methanesulfonate (mesylate) salt prepared from equimolar amounts of dabrafenib and methanesulfonic acid. Used for treatment of metastatic melanoma. | | 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. |
| Dabrafenib Mesylate(GSK-2118436B) Preparation Products And Raw materials |
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