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Khmelnitsky Y.L.,Circle Inc. | Michels P.C.,Circle Inc. | Cotterill I.C.,Circle Inc. | Eissenstat M.,Sequoia Pharmaceuticals Inc. | And 8 more authors.
Organic Process Research and Development | Year: 2011

A simple and efficient process has been developed to effect the kinetic resolution of the racemic alcohol 2 using immobilized lipase to afford the desired optically pure (R)-bis-tetrahydrofuran (bis-THF) alcohol 3, to facilitate the rapid progression of a clinical candidate. Rapid optimization and development of reproducible and scalable processes are essential to meet aggressive timeframes for preclinical, safety, and early clinical drug development. Process parameters were initially scoped and optimized using a combination of a rational bioprocess screening design and parallel microscale empirical studies, specifically accounting for scale-up and downstream processing considerations. The choices of reaction solvent, acyl donor, and immobilized biocatalyst proved to be critical factors in the design of a conveniently scalable and enantioselective enzymatic resolution process. The improved process was initially validated on 3-g and then 90-g scale in simple impeller-stirred reactors, exhibiting excellent reproducibility. This methodology was successfully implemented on a multikilogram scale to give the target alcohol 3 with >99% ee. © 2010 American Chemical Society.

Rajitha C.,Indus BioSciences Private Ltd | Rajitha C.,Jawaharlal Nehru Technological University Anantapur | Dubey P.K.,Jawaharlal Nehru Technological University Anantapur | Sunku V.,Indus BioSciences Private Ltd | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2011

The synthesis of novel 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives has been carried out using trifluoroacetic anhydride/phosphoric acid mediated C-C bond forming reaction as a key step. This method does not require the use of environmentally harmful AlCl 3 or moisture sensitive acid chloride. A number of compounds containing the benzooxazinone moiety attached to a five-membered central heterocyclic ring was synthesized and tested for their anti-cancer properties in vitro against three cell lines e.g. A549 (lung), DLD-1 (colorectal adenocarcinoma) and MV4-11 (acute myeloid leukemia). Some of them showed anti-cancer activities along with a number of reference compounds tested. Few of them showed promising anti-leukemic properties. A brief Structure-Activity-Relationship study within the series is presented. An imidazole derivative 9c containing benzene ring with a para-CF 3 group at C-2 position was identified as a potent anti-leukemic agent. © 2011 Elsevier Masson SAS. All rights reserved.

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