Biocatalytic routes to the synthesis of chiral pharmaceutical intermediates in ionic liquids

• Main Author: Roberts, Nicola Jean
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: UCL (University College London) 2005
• Subjects: Antarc*; Antarctica
• Online Access: https://discovery.ucl.ac.uk/id/eprint/1446552/1/Roberts.N.J_thesis.Redacted.pdf; https://discovery.ucl.ac.uk/id/eprint/1446552/

The main objective of this thesis is to identify a generic approach for the application of ionic liquids to bioconversions. Key factors for the operation of bioconversions in ionic liquids have been identified and product recovery options investigated. Two bioconversions were examined. The first was the hydrolytic resolution of racemic 2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-l ,4-benzodiazepine-2-acetic acid methyl ester (SB-235349) to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-l,4- benzodiazepine-2-acetic acid (SB-240101) by immobilised Candida antarctica lipase B, CALB (Novozyme 435), performed industrially in t-butanol. Initial studies showed this reaction occurred in several ionic liquids with different physico-chemical properties. Simply replacing the organic solvent with an ionic liquid under otherwise identical conditions reduced the rate of conversion and overall yield. The key factors influencing the rate and yield of this bioconversion in ionic liquids were the type of ionic liquid and the substrate solubility, the reaction temperature and the water content. The final optimised reaction in ionic liquids shows an eighteen-fold enhancement in product formation compared to the optimised t-butanol system. In order for ionic liquids to be applied commercially there are still many issues which still need to be resolved these include: the extraction of substrates and products from the ionic liquid media for down stream processing, and the recycle of the media for subsequent reactions. The next step having optimised the CALB bioconversion of SB- 235349 in ionic liquid media was to extract the SB-240101 product and the un-reacted SB-235349 substrate in order to recycle the ionic liquid. The SB-240101 produced by the reaction was removed by liquid-liquid extraction with 50mM bicarbonate buffer (pH 10); overall 93% of the SB-240101 produced was removed from the ionic liquid into the aqueous buffer phase. The un-reacted 2,3,4,5-tetrahydro-4-methyl-3-oxo-lH- 1,4-benzodiazepine-2-acetic acid methyl, ester (SB-240098) ...