934660-93-2

Basic information

• Product Name: XL518
• Synonyms: XL518;GDC-0973;RG7420;[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aMino]phenyl][3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl]Methanone;GDC-0973(XL-518);(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)Methanone;XL518 ,GDC-0973;CobiMetinib
• CAS NO: 934660-93-2
• Molecular Formula: C21H21F3IN3O2
• Molecular Weight: 531.3100196
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Protein Kinase Inhibitors and Activators;API;MAPK
• Mol File: 934660-93-2.mol

Chemical Properties

• Boiling Point: 565.9±50.0 °C(Predicted)
• Appearance: /
• Density: 1.706
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig
• PKA: 13.13±0.20(Predicted)
• CAS DataBase Reference: XL518(CAS DataBase Reference)
• NIST Chemistry Reference: XL518(934660-93-2)
• EPA Substance Registry System: XL518(934660-93-2)

Safety Data

• Hazardous Substances Data: 934660-93-2(Hazardous Substances Data)

Usage

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

Upstream product

• 934665-56-2 tert-butyl (S)-2-{1-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl]-3-hydroxy-3-azetidinyl}perhydropyridine-1-carboxylate 
• 29632-74-4 2-fluro-4-iodoaniline 
• 3105-95-1 pipecolinic acid 
• 934666-39-4 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate 
• 391211-97-5 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid 
• 28697-17-8 N-BOC-D-pipecolic acid 
• 61079-72-9 2,3,4,-trifluorobenzoic acid 
• 157373-08-5 2,3,4-trifluoro-benzoyl chloride 
• 106565-71-3 (3S,5R,8aS)-3-phenylhexahydro-2H-oxazolo[3,2-a]pyridine-5-carbonitrile 
• 1597407-55-0 3-((3S,5R,8aS)-5-cyano-3-phenyl-hexahydro-oxazolo[3,2-a] pyridin-5-yl)-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester 
• 1597407-56-1 3-hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]azetidine-1-carboxylic acid tert-butyl ester 
• 1597407-58-3 {3-hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanone 
• 26250-84-0 (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid 

Relevant articles and documents

PROCESS FOR THE PRODUCTION OF COBIMETINIB

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.

Preparation method of cobimetinib

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

Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines

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 cappi for nepal chemical synthesis method

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.

A 3 - (piperidin - 2 - yl) - azetidine - 3 - ol derivatives of synthetic method and use thereof

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

CRYSTALLINE FUMARATE SALT OF (S)-[3,4-DIFLUORO-2-(2-FLUORO-4-IODOPHENYLAMINO)PHENYL] [3-HYDROXY-3-(PIPERIDIN-2-YL) AZETIDIN-1-YL]-METHANONE

This disclosure relates to the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone. The disclosure also relates to pharmaceutical compositions comprising the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone. The disclosure also relates to methods of treating cancers comprising administering to a patient in need thereof the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone.

Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol

The invention discloses a method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol. The method comprises the following steps: condensing a compound S-N-Boc-piperidine-2-formic acid of a formula A and CDI so as to obtain a compound of a f

Synthesis method of cobimetinib

The invention discloses a synthesis method of cobimetinib. The method comprises the following steps: respectively carrying out salt forming reaction and bromination reaction on (R)-N-Boc-2-piperidinecarboxylic acid, silver nitrate (or mercuric oxide) and

Preparation method of cobimetinib

The invention discloses a preparation method of cobimetinib (Cobimetinib, XL518, GDC-0973) (I). The method includes the preparation steps of preparing an intermediate [2-oxo-2-((2S)-1-t-butyloxycarboryl-2-based]acetate through acyl cyanide formation, hydrolysis, esterification and Boc prortection with (2S)-2-pipecolic acid as the raw material, preparing an intermediate (2S)-1-t-butyloxycarboryl-2-(3-azetidinol-3-based)piperidine by conducting the addition reaction, the reduction action and the cyclization reaction on the intermediate body, and making the intermediate (2S)-1-t-butyloxycarboryl-2-(3-azetidinol-3-based)piperidine and a side chain subjected to a condensation reaction to obtain the cobimetinib (I). According to the preparation method, raw materials can be easily obtained, the process is simple, and the method is economical, environmentally friendly and suitable for industrialized production.

NOVEL PROCESS FOR MAKING COMPOUNDS FOR USE IN THE TREATMENT OF CANCER

Disclosed herein is a process of making a compound of formula I The compound of formula I is an inhibitor of MEK and thus can be used to treat cancer.