David O. Morgan

The use of a novel microreactor for high throughput continuous flow organic synthesis

Abstract The aim of this study was to investigate the performance characteristics of a flow injection microreactor with reference to both the chemistry and reactor design using a model system, the established synthesis of 4-cyanobiphenyl based on a modified Suzuki coupling of an aryl halide and an organoboron compound. The catalytic reaction was carried out in micro-channels (300 μm wide and 115 μm deep) etched into glass and sealed with a top plate. The mobility of the reagent solutions was achieved using electroosmotic flow (EOF) assisted by the incorporation of a microporous silica structure within the microreactor channels, which acted as both a micro-pump and an immobilisation technique for the catalyst bed (1.8% palladium on silica). The yield of 4-cyanobiphenyl was determined by GC–MS. The synthesis of 4-cyanobiphenyl at room temperature in a flow injection microreactor, using a supported catalyst, without the addition of a base gave a product yield of 67±7% ( n =6). This was achieved by injecting 4-bromobenzonitrile for 5 s, with a 25-s injection interval, into a continuous stream of phenylboronic acid. A series of injections were performed over a 25-min period and the product collected for analysis. Palladium contamination in the crude product was found to be in the range of 1.2–1.6 ppb, determined using ICP–MS, indicating a low leach rate from the immobilised catalyst. A conventional laboratory batch scale method was also performed for the same synthesis using the identical conditions as those used in the flow injection microreactor, with and without the addition of a base, at both room and elevated temperatures (75–80°C) in an inert atmosphere under reflux for 8 h. The product yield for the non-optimised bulk reaction was 10% (determined by GC–MS), significantly lower than with the flow injection microreactor illustrating the potential of microreactors for clean efficient synthesis.

The generation of concentration gradients usingelectroosmotic flow in micro reactors allowing stereoselective chemicalsynthesis

The stereoselective control of chemical reactions has been achieved by applying electrical fields in a micro reactor generating controlled concentration gradients of the reagent streams. The chemistry based upon well-established Wittig synthesis was carried out in a micro reactor device fabricated in borosilicate glass using photolithographic and wet etching techniques. The selectivity of the cis (Z) to trans (E) isomeric ratio in the product synthesised was controlled by varying the applied voltages to the reagent reservoirs within the micro reactor. This subsequently altered the relative reagent concentrations within the device resulting in Z/E ratios in the range 0.57-5.21. By comparison, a traditional batch method based on the same reaction length, concentration, solvent and stoichiometry (i.e., 1.0:1.5:1.0 reagent ratios) gave a Z/E in the range 2.8-3.0. However, when the stoichiometric ratios were varied up to ten times as much, the Z/E ratios varied in accordance to the micro reactor i.e., when the aldehyde is in excess, the Z isomer predominates whereas when the aldehyde is in low concentrations, the E isomer is the more favourable form. Thus indicating that localised concentration gradients generated by careful flow control due to the diffusion limited non-turbulent mixing regime within a micro reactor, leads to the observed stereo selectivity for the cis and trans isomers.

Comparison of neural network predictors in the classification of tracheal-bronchial breath sounds by respiratory auscultation

Despite extensive research in the area of identification and discrimination of tracheal-bronchial breath sounds by computer analysis, the process of identifying auscultated sounds is still subject to high estimation uncertainties. Here we assess the performance of the relatively new constructive probabilistic neural network (CPNN) against the more common classifiers, namely the multilayer perceptron (MLP) and radial basis function network (RBFN), in classifying a broad range of tracheal-bronchial breath sounds. We present our data as signal estimation models of the tracheal-bronchial frequency spectra. We have examined the trained structure of the CPNN with respect to the other architectures and conclude that this architecture offers an attractive means with which to analyse this type of data. This is based partly on the classification accuracies attained by the CPNN, MLP and RBFN which were 97.8, 77.8 and 96.2%, respectively. We concluded that CPNN and RBFN networks are capable of working successfully with this data, with these architectures being acceptable in terms of topological size and computational overhead requirements. We further believe that the CPNN is an attractive classification mechanism for auscultated data analysis due to its optimal data model generation properties and computationally lightweight architecture.

A new synthesis of the GPIIb/IIIa receptor antagonist SB-214857-A

A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised lipase enzyme and a palladium-catalysed aminocarbonylation reaction.

Alkoxy radicals in organic synthesis. A novel approach to a key intermediate in milbemycin chemistry

Abstract The fragmentation of nitrate ester ( 2 ) via an alkoxy radical to lactone ( 3 ) is described. This lactone is a key intermediate in the synthesis of semisynthetic milbemycins.

Spiroacetal synthesis from a key lactone intermediate leading to novel C24 and C25-substituted milbemycins

Abstract The lactone intermediates (3), (4) and (5) are converted via lithium acetylide chemistry to a range of novel C24 and C25-substituted milbemycins. The methdology has been extended to afford milbemycins containing 6,5-spiroacetal units.

A mild and efficient method for the formation of a key intermediate in penem chemistry

Abstract A mild, rapid and efficient method for the formation of phosphoranes 2 from oxalimides 1 is described. These phosphoranes can be cyclized to provide penems 3 .

Micro-reactor synthesis: synthesis of cyanobiphenyls using a modified Suzuki coupling of an aryl halide and aryl boronic acid

The synthesis of cyanobiphenyls using a modified Suzuki coupling was performed in a micro-reactor system (channel geometries of 300 μm wide and 115 μm deep) etched in borosilicate glass, using a photolithographic patterning technique [1]. The organic starting reagents were moved by electro-osmotic flow (EOF). A micro-porous silica structure [2] was used within the channels, to act as a micro-pump and also assist in the immobilisation process for the heterogeneous catalyst bed.

Synthesis of an α-(aminooxy)arylacetic ester by the reaction of an α-diazo ester with n-hydroxyphthalimide

The α-diazo esters (6) and (7) react, in the absence of any catalyst, with a variety of HONR2 and HONCR2 compounds to give the 0-alkylated adducts (8) to (16). In particular, reaction of (7) with N-hydroxyphthalimide in refluxing benzene followed by deprotection gives the title compound (1)

Semi-synthetic C23-substituted milbemycins via spiroacetal cleavage and resynthesis

Abstract The lactone intermediates (2) and (3) are converted by lithium acetylide chemistry followed by mercury catalysed hydration to novel semi-synthetic 23-oxo C24 and C25 substituted milbemycins (7).