Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

EducaçãoQuim. Nova 2015, 38(2), 285-287

Luís M. R. Solano^I; Nuno M. T. Lourenço^II,*

This paper describes a multi-step chemo-enzymatic synthesis of antidepressant drug precursors.

http://dx.doi.org/10.5935/0100-4042.20140306

Publicado online: novembro 13, 2014

Quim. Nova, Vol. 38, No. 2, 285-287, 2015

Educação http://dx.doi.org/10.5935/0100-4042.20140306

*e-mail: nmtl@tecnico.ulisboa.pt

ENZYMATIC RESOLUTION OF ANTIDEPRESSANT DRUG PRECURSORS IN AN UNDERGRADUATE LABORATORY

Luís M. R. Solanoa and Nuno M. T. Lourençob,* a Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal b Departamento de Bioengenharia, Instituto de Biotecnologia e Bioengenharia, Instituto Superior Técnico, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal

Recebido em 07/07/2014; aceito em 17/09/2014; publicado na web em 13/11/2014

The use of biocatalysts in synthetic chemistry is a conventional methodology for preparing enantiomerically enriched compounds. Despite this fact, the number of experiments in chemical teaching laboratories that demonstrate the potential of enzymes in synthetic organic chemistry is limited. We describe a laboratory experiment in which students synthesized a chiral secondary alcohol that can be used in the preparation of antidepressant drugs. This experiment was conducted by individual students as part of a Drug Synthesis course held at the Pharmacy Faculty, Lisbon University. This laboratory experiment requires six laboratory periods, each lasting four hours. During the first four laboratory periods, students synthesized and characterized a racemic ester using nuclear magnetic resonance spectroscopy and gas chromatography. During the last two laboratory periods, they performed enzymatic hydrolysis resolution of the racemic ester using Candida antarctica lipase B to yield enantiomerically enriched secondary alcohol. Students successfully prepared the racemic ester with a 70%-81% overall yield in three steps. The enzymatic hydrolysis afforded (R)- secondary alcohol with good enantioselectivity (90%–95%) and reasonable yields (10%–19%). In these experiments, students were exposed to theoretical and practical concepts of aromatic acylation, ketone reduction, esterification, and enzymatic hydrolysis. Keywords: sec-alcohols; esters; lípase; enantiomers; resolution.

READ AT

http://quimicanova.sbq.org.br/imagebank/pdf/v38n2a20.pdf

 

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Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions

Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions

Frederico Castelo Ferreira et al

http://berg.ist.utl.pt/members/fferreira.html

see article at

Org. Process Res. Dev. 10, 784-793 (2006)

http://pubs.acs.org/doi/abs/10.1021/op0600456?prevSearch=enantiomer%2Brecycling&searchHistoryKey=

This paper describes a liquid-phase process for recycling of resolving agents used in the diastereomeric resolution of chiral bases. The process is applicable to the resolution of any chiral base by an organic acid resolving agent which takes place in a polar solvent. The resolving agent is first of all separated from the diastereomeric complex by addition of aqueous HCl. The initial stage of process development is selection of a water-immiscible extracting organic solvent to recover the resolving agent from the resulting acidic aqueous solution. Either distillation or organic solvent nanofiltration is subsequently used to exchange the resolving agent from the extracting organic solvent back into the polar resolution solvent. This choice between these two technologies for solvent exchange depends on the relative boiling points of the two solvents. The resolution of PPI2, a racemic amine by di-p-toluoyl-l-tartaric acid (DTTA), was selected as an example of a typical resolution used in an organic process. Using the conventional process, this resolution requires 1.75 mol equiv of DTTA for each mole of racemic base fed to resolution, and thus the bulk of the DTTA ends up in the mother liquor. Using the recycling process, DTTA from both mother liquor and crystals was recovered and recycled over seven consecutive resolutions, while the final product enantiomeric excess and resolution yield were maintained at 100% and 40%, respectively. In this way the DTTA requirement was decreased from 1.75 to 0.26 DTTA mol equiv, reducing the amount of fresh resolving agent needed for each resolution by 85%.