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Title: Catalytic asymmetric transformation of chiral amines by crystallisation with in-situ racemisation of conglomerates
Author: Baldwin, Peter
ISNI:       0000 0004 6421 7604
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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Optically pure chiral molecules account for an increasing number of active pharmaceutical ingredients (API’s); yet despite giving high enantiomeric excesses, existing techniques for obtaining pure enantiomers are hindered by low yields, high complexities, large waste streams, and hence high operational costs. Diastereomic crystallisation is the most commonly used resolution method and is capable of giving high enantiomeric excesses yet many additional processing stages are required to recover the desired enantiomer. If a racemate exists as a conglomerate, i.e. a mechanical mixture of discreet homochiral crystals, preferential crystallisation may be employed. However, both techniques are limited to a theoretical maximum yield of 50%. Coupling resolution by preferential crystallisation with organometallic catalysed racemisation in a crystallisation induced asymmetric transformation (CIAT) process may overcome these problems potentially giving a theoretical quantitative yield of a chosen enantiomer from an initially racemic solution in a single, efficient crystallisation step. CIAT was attempted under isothermal and polythermal conditions using the conglomerate diol hydrobenzoin and the organometallic catalyst chloro(indenyl)-bis-(triphenylphosphine)-ruthenium(II) for solution phase racemisation. Optically pure product crystals were obtained with chemical purities of up to 99.71% when isothermal temperature programmes were employed in short process runs yet only relatively low yields could be recovered. Under polythermal conditions, crystal yields were improved significantly whilst increases of up to 61.57% were observed in the total quantity of the desired (S,S)-hydrobenzoin enantiomer present in both the solid and solution phases at the end of the process indicating that CIAT had occurred. However, in all of the polythermal runs trialled, nucleation of the undesired counter enantiomer and meso forms of hydrobenzoin could not be avoided. This was found to be a result of the catalysts being completely consumed in a side reaction leading to racemisation ceasing to progress after approximately 1-2 h. Hence, as the seeded enantiomer continued to be crystallised, the concentrations of the undesired species were not reduced through transformation leading to them reaching their metastable solubility limits. CIAT of hydrobenzoin was also attempted using chloromonocarbonyltriphenylphosphine-(1,2,3,4,5-pentaphenylcyclopentadienyl)-ruthenium(II) which was shown to remain active for up to 5 days. However, over the course of the CIAT experiments which exceeded 2 h, hydrobenzoin in solution was converted to benzaldehyde via C-C bond cleavage which resulted in the seed crystals being completely dissolved.
Supervisor: Lai, Xiaojun ; Blacker, John ; Borissova, Antonia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available