934660-93-2 Usage
Description
Cobimetinib, codeveloped by
Genentech and Exelixis, was approved in August 2015 in
Switzerland and November 2015 in the U.S. and Europe for the
treatment of unresectable or metastatic BRAFV600 mutationpositive
melanoma when used in combination with vemurafenib. Cobimetinib is a potent, highly selective reversible
inhibitor of mitogen-activated protein kinases (MEK) 1 and
2,120 which serves to inhibit phosphorylation of ERK1/2,121
disrupting the MAPK pathway which is responsible for cell
proliferation, cell survival, and migration.122 Combination of
cobimetinib with vemurafenib, an important BRAF inhibitor,123
enables targeting of multiple points on the MAPK pathway,
leading to overall enhanced tumor cell apoptosis and response
as compared to stand-alone treatment with vemurafenib.124
Specifically, in a representative trial of previously untreated
patients with BRAFV600 mutation-positive, unresectable, stage
IIIc or IV melanoma, combination of these two therapies led to
a significantly improved progression-free survival and overall
response rate versus patients treated only with vemurafenib.
Uses
A potent, selective, 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 (it is important to note that the authors offer no
comment as to the regioselectivity of this aromatic substitution
reaction). While the drug reportedly exists as a fumarate salt,
no synthetic reports describing the conversion of cobimetinib to the corresponding fumarate salt were available in the
chemical literature to our knowledge at the time of publication.
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
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.
supporting information, (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.
Preparation method of cobimetinib
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Paragraph 0028; 0035; 0036; 0037; 0049; 0054; 0055, (2019/02/04)
The invention discloses a preparation method of cobimetinib. The preparation method comprises the following steps of (1) performing oxidative coupling cyclization on acetone and ammonia water under the conditions of catalysis by iodized salt and protonic
A cappi for nepal chemical synthesis method
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, (2018/01/13)
The invention belongs to the field of chemical synthesis and specifically relates to a preparation method for cobimetinib. The method comprises the following steps: by taking 2,3,4-benzyl trifluorobenzoate as an initial raw material, performing substitution reaction, deprotection reaction, amidation reaction and catalytic addition reaction, thereby obtaining the cobimetinib. The method provided by the invention has the advantages of easily-obtained and low-cost raw materials, short process flow, easiness in operation of industrial reaction, high yield, environmental protection and suitability for industrial batch production.
