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This paper describes ideas together with preliminary experimental results for applying solvent nanofiltration to liquid phase organic synthesis reactions. Membranes for organic solvent nanofiltration have only recently (during the 1990s) become available and, to date, have been applied primarily to food processing (vegetable oil processing, in particular) and refinery processes. Applications to organic synthesis, even at a laboratory feasibility level, are few. However, these membranes have great potential to improve the environmental performance of many liquid phase synthesis reactions by reducing the need for complex solvent handling operations. Examples that are shown to be feasible are solvent exchanges, where it is desired to swap a high molecular weight molecule from one solvent to another between separate stages in a complex synthesis, and recycle and reuse of homogeneous catalysts. In solvent exchanges, nanofiltration is shown to provide a fast and effective means of swapping from a high boiling point solvent to a solvent with a lower boiling point—this is a difficult operation by means of distillation. Solvent nanofiltration is shown to be able to separate two distinct types of homogeneous catalysts, phase transfer catalysts and organometallic catalysts, from their respective reaction products. In both cases the application of organic solvent nanofiltration allows several reuses of the same catalyst. Catalyst stability is shown to be an essential requirement for this technique to be effective. Finally, we present a discussion of scale‐up aspects including membrane flux and process economics.

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Organic solvent nanofiltration (OSN) is a new membrane technology with many applications in pharmaceutical and fine chemicals development and manufacture, from laboratory through production scales. One application of particular industrial relevance is the ability to recover and recycle homogeneous catalysts, in particular asymmetric, organometallic, homogeneous transition metal catalysts. Industrial application of this group of catalysts is often limited due to the cost of applying these catalysts to single reactions and the subsequent product yield losses associated with removal of the catalyst from solution. OSN provides a technique that can maximise the value of the catalyst through catalyst recycle from one reaction batch to the next, whilst minimising the concentration of catalyst present in the reaction product. This contribution describes the development and demonstration of OSN catalyst recycle on an example catalytic system, the homogeneous, asymmetric hydrogenation of dimethyl itaconate (DMI) to dimethyl methylsuccinate (DMMS) with Ru-BINAP. The first step of the development process was to demonstrate that Ru-BINAP was sufficiently stable that the process concept, i.e., catalyst recycling, was feasible. A dilute solution (0.8 wt %) of DMI in methanol with a high catalyst loading (S/C ) 500) was used, and 14 successive reactions were carried out with constant reaction rate and without yield or enantiomeric excess (ee) reduction. In industrial practice, the goal is always to operate a reaction at the highest, practical S/C ratio, and thus the next stage of development was to optimise the S/C ratio. The limiting, practical S/C ratio was found to be 7000. The process was then run with the optimised dilute reaction system, which allowed 10 reaction cycles to be carried out with only 20% addition of the initial (reaction 1) mass of catalyst to reactions 2-10 to maintain reaction rate, conversion, and ee. This leads to a 5 times increase in the overall S/C ratio. In addition, this optimisation reduced the amount of metal present in the product solution from 130 µg Ru per gram of product to <6 µg Ru per gram of product. The process was then scaled up to an industrially relevant substrate concentration (20 wt % DMI in methanol), and it was found that both the reaction (in terms of reaction rate, conversion, and yield) and the ability to recycle the catalyst were unaffected by the scale-up in concentration.

Oxazolo [2,3-a]isoindol-5-one derivatives exhibit anticonvulsant and anti-inflammatory activities. 1 The chemistry and reactivity of isoindolinone ring system is an area of interest because of its biological activity. 2 Recently Allin and coworkers 3 have reported a new synthesis of non-racemic isoindolinone targets through application of oxazolo-[2,3-a]isoindolinones as N-acyl iminium ion precursors in reactions with carbon and hydride nucleophiles. We had earlier reported the formation of a novel 10 membered chiral ring system 4 while attempting to synthesise oxazolo-[2,3-a]isoindol-5(9bH)-one using (R) or (S)-2-amino-1butanol via Meyers methodology 5 involving reduction of the imide and cyclisation using trifluoro acetic acid. The phenyl group was introduced by the addition of phenyl magnesium bromide (c) to (R) or (S)-2-(1-hydroxy)phthalimides 3a or 3b. These were derived from phthalic anhydride 1 and (R)-(-)-2amino-1-butanol 2a or (S)-(+)-2-amino-1-butanol 2b. The resulting dihydroxy compounds 4a or 4b were not isolated, but were directly subjected to acid-catalysed cyclisation to furnish the 9b-phenyl substituted oxazolo[2,3a] isoindolinones 10a or 10b in 40-50% yields. In a similar fashion the addition of p-fluoro(d), p-chloro(e), p-methoxy(f) and p-methyl(g) substituted phenyl magnesium bromides furnished the corresponding 9b-substituted-phenyl substituted oxazolo[2,3a] isoindolinones 11a-14a or 11b-14b respectively (Scheme 1).Compound 10b was subjected to a single crystal X-ray diffraction analysis 6 and its structure was solved and refined by SHELX 97 program 7 (Fig. 1). The absolute configuration of the phenyl substituted oxazolo[2,3-a]isoindolin-5-one was found to be (3S, 9bR).