- PROCESS FOR THE PRODUCTION OF COBIMETINIB
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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.
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- Preparation method of cobimetinib
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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
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Paragraph 0028; 0035; 0036; 0037; 0049; 0054; 0055
(2019/02/04)
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- Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines
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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.
- Fawcett, Alexander,Murtaza, Amna,Gregson, Charlotte H. U.,Aggarwal, Varinder K.
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- A cappi for nepal chemical synthesis method
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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.
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- A 3 - (piperidin - 2 - yl) - azetidine - 3 - ol derivatives of synthetic method and use thereof
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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
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- CRYSTALLINE FUMARATE SALT OF (S)-[3,4-DIFLUORO-2-(2-FLUORO-4-IODOPHENYLAMINO)PHENYL] [3-HYDROXY-3-(PIPERIDIN-2-YL) AZETIDIN-1-YL]-METHANONE
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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.
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- Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol
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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
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- Synthesis method of cobimetinib
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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
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- Preparation method of cobimetinib
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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.
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- NOVEL PROCESS FOR MAKING COMPOUNDS FOR USE IN THE TREATMENT OF CANCER
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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.
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Paragraph 000143
(2014/05/07)
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- Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)
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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
- Rice, Kenneth D.,Aay, Naing,Anand, Neel K.,Blazey, Charles M.,Bowles, Owen J.,Bussenius, Joerg,Costanzo, Simona,Curtis, Jeffry K.,Defina, Steven C.,Dubenko, Larisa,Engst, Stefan,Joshi, Anagha A.,Kennedy, Abigail R.,Kim, Angie I.,Koltun, Elena S.,Lougheed, Julie C.,Manalo, Jean-Claire L.,Martini, Jean-Francois,Nuss, John M.,Peto, Csaba J.,Tsang, Tsze H.,Yu, Peiwen,Johnston, Stuart
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supporting information; experimental part
p. 416 - 421
(2012/06/30)
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- METHODS OF USING MEK INHIBITORS
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The present invention provides methods of treating cancer by administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.
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Page/Page column 406
(2008/12/06)
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- METHODS OF USING COMBINATIONS OF MEK AND JAK-2 INHIBITORS
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A method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a MEK compound of Formula I(M), or a pharmaceutical composition comprising a therapeutically effective amount of a MEK compound of Formula I(M) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 compound of Formula I(J), or a pharmaceutical composition comprising a therapeutically effective amount of a JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, wherein the MEK compound of Formula I(M) and JAK-2 compound of Formula I(J) are as defined in the specification.
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Page/Page column 253-254
(2008/12/04)
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