Roberts, Nicola Jean; (2005) Biocatalytic routes to the synthesis of chiral pharmaceutical intermediates in ionic liquids. Doctoral thesis , UCL (University College London).

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Abstract

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) was removed by liquid- liquid extraction with isopropyl alcohol, and 91% was removed from the ionic liquid. The ionic liquid was then regenerated with sodium hydroxide for recycle. The results from the bioconversion with fresh and recycled ionic liquid were almost identical, in both cases around l.8g.L-1 of product was produced in 6 hours. The two-phase extractions were subsequently studied in the Lewis cell, and the mass transfer rate (K0) examined for the extraction of both the substrate and the product from the ionic liquid. Values of K0 determined in the Lewis cell over the Reynolds number range for which a flat, non-perturbed, interface could be maintained were in the range 1.0 - 3.5 X 10-6 m.s-1 for both product and substrate extraction. In both extraction experiments there was a linear increase in K0 with Reynolds number. The second bioconversion the thymidine phosphorylase catalysed synthesis of thymidine from thymine, which is traditionally performed in aqueous media, was then examined in ionic liquids. Initial investigations of this conversion step showed that replacing the aqueous media with an ionic liquid like [BMIM][PF6] under otherwise identical reaction conditions reduced the overall yield, which is attributed to the low solubility of the reagents in this ionic liquid. As the first constraint of the aqueous system was the solubility of the substrates and products; work then focused on those ionic liquids that showed a high solubility for thymine and especially thymidine. A study of the conversion in these high solubility ionic liquids showed conversion to the same degree as that demonstrated in aqueous media. An examination of product recovery from [EMIM][tosylate] following the thymidine transformation showed that the most likely method of product recovery was adsorption to an anion exchange resin 1-X8. In summary the results presented in this thesis show that ionic liquids offer significant advantages as alternative reaction media in industrial bioconversions. These are related to the excellent solvation properties of ionic liquids, and the tunable physicochemical properties of ionic liquids such as miscibility (or immiscibility) with water by changes in the anion or cation. Overall this thesis has identified generic procedures for the design of bioconversions and product recovery options in ionic liquids that have been exemplified using two different bioconversion systems.

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