934660-93-2 Usage
Description
XL518, also known as Cobimetinib, is a potent, highly selective, and reversible inhibitor of mitogen-activated protein kinases (MEK) 1 and 2. It was co-developed by Genentech and Exelixis and approved for the treatment of unresectable or metastatic BRAFV600 mutation-positive melanoma when used in combination with vemurafenib. XL518 serves to inhibit the phosphorylation of ERK1/2, disrupting the MAPK pathway responsible for cell proliferation, cell survival, and migration.
Uses
Used in Oncology:
XL518 is used as a potent, selective, and orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. It inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well-tolerated doses.
Clinical Use
Protein kinase inhibitor:
Treatment of unresectable or metastatic melanoma
with a BRAF V600 mutation in combination with
vemurafenib
Synthesis
Structurally, cobimetinib features an interesting azetidinol
substructure appended to the 2-position of a piperidine,
rendering the 2-carbon of the piperidine as a stereogenic
center bearing the (S)-configuration. While the early discovery
routes to cobimetinib relied on a piperidine resolution-based
route for accessing the cobimetinib core, the scale route
to this drug employs an impressive N-cyanomethyl oxazolidine
chiral auxiliary-mediated sequence to induce strereocontrol,
generating the requisite stereocenter with excellent selectivity
and requiring no chromatographic purification in the overall
synthetic sequence. Toward this end, the most likely scale
synthetic approach was initiated with deprotonation of
commercially available (3S,5R,8aS)-3-phenyl-hexahydrooxazolo[
3,2-a]pyridine-carbonitrile (180), followed
by addition of commercial 3-oxo-azetidine-1-carboxylic acid
tert-butyl ester (181), yielded 182 in high purity (92%) after
distillation and providing a rapid route to the core structure of
cobimetinib. One-pot ring opening and reduction of 182 was
accomplished by exposing this hemiaminal to acetic acid and
sodium cyanoborohydride, giving rise to intermediate 183. This
carbamate could be further reacted with aqueous HCl in
toluene to liberate the azetidine amine salt in high purity
(97.6%), which underwent immediate acylation with commercially
available 2,3,4-trifluoro-benzoyl chloride (184) to enable
formation of intermediate 185 in 85% purity after aqueous
workup. Reductive cleavage of the chiral auxiliary of 185 with
Pd/C and H2 under aqueous acidic conditions (AcOH, aq
HCl) yielded the desired piperidine amine, which could be
isolated as a solid (99.6% pure) after trituration with aqueous
HCl. Finally, aromatic fluoride substitution with commercially
available aniline 186 under basic conditions provided
cobimetinib in 99.7% purity after slow precipitation from
toluene (
Drug interactions
Potentially hazardous interactions with other drugs
Antifungals: concentration increased by itraconazole.
Antipsychotics: increased risk of agranulocytosis -
avoid.
Metabolism
Metabolised by oxidation by CYP3A and glucuronidation
by UGT2B7. Extensively metabolised and eliminated in
faeces
Check Digit Verification of cas no
The CAS Registry Mumber 934660-93-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,3,4,6,6 and 0 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 934660-93:
(8*9)+(7*3)+(6*4)+(5*6)+(4*6)+(3*0)+(2*9)+(1*3)=192
192 % 10 = 2
So 934660-93-2 is a valid CAS Registry Number.
934660-93-2Relevant articles and documents
PROCESS FOR THE PRODUCTION OF COBIMETINIB
-
, (2019/05/22)
The present invention relates to a novel route of synthesis for the production of enantiomerically pure Cobimetinib, new intermediates in the synthesis of Cobimetinib and an amorphous Cobimetinib hemifumarate salt comprising a high salt content.
Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines
Fawcett, Alexander,Murtaza, Amna,Gregson, Charlotte H. U.,Aggarwal, Varinder K.
, (2019/03/26)
Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.
A 3 - (piperidin - 2 - yl) - azetidine - 3 - ol derivatives of synthetic method and use thereof
-
, (2017/12/05)
The invention discloses a synthesis method of 3-(piperidyl-2-yl)-azetidinyl-3-ol derivatives and a method for synthesizing Cobimetinib from the compounds. The method comprises the following steps: by using compounds F as an initial raw material, carrying
