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Synthesis 2012(4): 635-647  
DOI: 10.1055/s-0031-1289676
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Scale-Up of Flow-Assisted Synthesis of C 2-Symmetric Chiral PyBox Ligands

Claudio Battilocchioa,c, Marcus Baumanna, Ian R. Baxendalea, Mariangela Biavac, Matthew O. Kitchinga, Steven V. Leya, Rainer E. Martin*b, Stephan A. Ohnmachtb, Nicholas D. C. Tappina
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
e-Mail: theitc@ch.cam.ac.uk;
b F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Chemistry Technology and Innovation, 4070 Basel, Switzerland
c Department of Pharmaceutical Chemistry and Technology, Sapienza University of Rome, Rome, Italy
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Publikationsverlauf

Received 19 November 2011
Publikationsdatum:
25. Januar 2012 (online)

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Abstract

A series of PyBox ligands were prepared from commercially available chelidonic acid by a multistep flow sequence using mesoreactor technology. A chloro group introduced onto the ligand scaffold was subsequently exploited to give amine derivatives ready for immobilization through microencapsulation technologies.

Key words

ligands - macrocycles - flow chemistry - solid-supported reagent - asymmetric synthesis - scale up

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12

The use of a standard T or Y union gave rise to problems of back-mixing and build-up of blockages in the flow channel.

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Commercially available from TCI Europe: Vilsmeier reagent N-(chloromethylene)-N-methylmethanaminium chloride [CAS Reg. No. 3724-43-4].

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The Vapourtec R2+/R4 flow system used in this study is commercially available from Vapourtec; Web site: http://www.vapourtec.co.uk.

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Quadrapure-DMA. Available from Johnson Matthey, see: http://www.scavengingtechnologies.com/site.asp?id = 1297&pageid = 1299.