Tuesday 31 May 2016

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

image file: c6re00059b-f1.tif


React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B, Paper
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows, Richard A. Bourne
Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.
Paper

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

*Corresponding authors
aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: r.a.bourne@leeds.ac.uk
bDepartment of Chemistry, Faraday Building, Lancaster University, Lancaster, UK
cSchool of Chemical and Process Engineering, University of Leeds, Leeds, UK
dAstraZeneca Pharmaceutical Development, Silk Road Business Park, Macclesfield, UK
React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B
http://pubs.rsc.org/en/Content/ArticleLanding/2016/RE/C6RE00059B#!divAbstract
str1
 Scheme 1 Synthesis of the model acrylamide 6 via the β-chloroamide 5 intermediate.
image file: c6re00059b-s1.tif

 Scheme 2 Proposed mechanisms to dimers 8a and 8b. The observation of a peak corresponding to 7suggested a Rauhut–Currier mechanism to 8b but subsequent LC-MS-MS analysis showed the major dimer to most likely be 8a. All observed peaks from offline LC-MS are displayed.
image file: c6re00059b-s2.tif


///////Self-optimisation, synthesis, EGFR kinase inhibitor, AZD9291,  automated flow reactor

Friday 13 May 2016

Small but Mighty: Boron Nanoparticles

Small but Mighty: Boron Nanoparticles







Nanoparticles for hydrogen generation from water at room temperature

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http://www.chemistryviews.org/details/news/9273321/Small_but_Mighty_Boron_Nanoparticles.html



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Catalytic Nanotube Reactors

Catalytic Nanotube Reactors







Iron-noble metal nanoparticles in silica nanotubes catalyze styrene hydrogenation

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http://www.chemistryviews.org/details/ezine/9297261/Catalytic_Nanotube_Reactors.html



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Alkenylation of Pyridylmethylesters







Alkenylation of Pyridylmethylesters

Palladium-catalyzed vinylation under mild conditions

Read more

http://www.chemistryviews.org/details/news/9301151/Alkenylation_of_Pyridylmethylesters.html



Sunday 8 May 2016

A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines

Green Chem., 2016, 18,2642-2646
DOI: 10.1039/C6GC00497K, Communication
Xiaofeng Zhang, Sanjun Zhi, Wei Wang, Shuai Liu, Jerry P. Jasinski, Wei Zhang
A pot-economical synthesis involving two [3 + 2] cycloadditions for diastereoselective synthesis of novel triazolobenzodiazepine-containing polycyclic compounds.
The content of this RSS Feed (c) The Royal Society of Ch

A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines



A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines

Xiaofeng Zhang,a   Sanjun Zhi,b   Wei Wang,c   Shuai Liu,a  Jerry P. Jasinskid and   Wei Zhang*a  
*
Corresponding authors
a
Centre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, USA 
E-mail: wei2.zhang@umb.edu
b
Jiangsu Key Laboratory for the Chemistry of Low-Dimensional Materials, Huaiyin Normal University, Huaian, PR China
c
School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, PR China
d
Department of Chemistry, Keene State College, Keene, USA
Green Chem., 2016,18, 2642-2646

DOI: 10.1039/C6GC00497K





















A pot-economical synthesis involving sequential [3 + 2] cycloadditions of an azomethine ylide and an azide–alkyne (click reaction) has been developed for diastereoselective synthesis of novel triazolobenzodiazepine-containing polycyclic compounds. A new example of catalyst-free click chemistry of non-strained alkynes is also disclosed.







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