In-line purification

The systems described in Scheme 4.49 are for simple single-step transformations, typically with in-line purification however, the real opportunities presented by flow techniques will be multistep transformations occurring both in series and in parallel. Initial work in this field has already resulted in the total synthesis of natural products, such as grossamide [88] and ( )-oxomaritidine [89], and the drug candidate BMS-275291 [90], which are discussed later. 

AD) and the application of a catch-and-release procedure using a supported boronic acid to effect in-line purification of the diol 20 (Scheme 5). The enantiomer of 20 could readily be obtained through the use of AD-mix-p in the Sharpless asymmetric dihydroxylation reaction. The two alcohol groups of the diol could subsequently be differentiated using an enzymatic selective protection. 

In a final example, Ladlow [61] reported an automated, polymer-assisted strategy for the synthesis of 2-alkylthiobenzimidaoles and N,N -dialkylbenzimidazolin-2-ones (Scheme 8.46). This approach incorporates in-line purification utilizing resin-... 

Scheme 8.46 In-line purification utilizing resin-bound scavengers towards library synthesis.

A., Bertolani, A., Molinari, F., and Conti, P. (2012) An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor. 

Chapters 1 and 2 have been reorganised and updated in line with recent developments. A new chapter on the Future of Purification has been added. It outlines developments in syntheses on solid supports, combinatorial chemistry as well as the use of ionic liquids for chemical reactions and reactions in fluorous media. These technologies are becoming increasingly useful and popular so much so that many future commercially available substances will most probably be prepared using these procedures. Consequently, a knowledge of their basic principles will be helpful in many purification methods of the future. 

A potential problem encountered in these determinations is the ion suppression encountered in the presence of polar/ionic interfering materials which compete with the analyte(s) for ionization (see Section 4.7.2 earlier). Many of these analyses therefore involve some degree of off-line purification and/or an appropriate form of chromatography. Since it is not unusual to encounter closely related compounds that are not easily separated, it is also not unusual to employ both of these approaches, as in the following example. This illustrates the use of HPLC as a method of purification and demonstrates that highly efficient separations are not always required for valuable analytical information to be obtained. 

The dominant mechanism of purification for column crystallization of solid-solution systems is recrystallization. The rate of mass transfer resulting from recrystallization is related to the concentrations of the solid phase and free liquid which are in intimate contact. A model based on height-of-transfer-unit (HTU) concepts representing the composition profile in the purification section for the high-melting component of a binary solid-solution system has been reported by Powers et al. (in Zief and Wilcox, op. cit., p. 363) for total-reflux operation. Typical data for the purification of a solid-solution system, azobenzene-stilbene, are shown in Fig. 20-10. The column crystallizer was operated at total reflux. The solid line through the data was com-putecfby Powers et al. (op. cit., p. 364) by using an experimental HTU value of 3.3 cm. 

At Merck KGaA in Darmstadt (Germany), in-line UV spectroscopy has been used for monitoring a distillation setup for solvent purification." A transmission probe was implemented at the top of the column. Solarization-resistant UV fibers guided the light to a diode array spectrometer. From the spectra, a quality parameter was extracted and fed to the process control system (PCS). As an example, the quality parameter would exhibit a transient behavior upon column startup. Below a defined threshold value of the parameter, the PCS would assume sufficient product quality and switch the exit stream from waste to product collection. The operation of the spectrometer does not take place in a direct manner, but rather via the PCS. 

Since the experimental conditions for the traditional Biginelli reaction are quite straightforward, small libraries of DHPMs are readily accessible by parallel synthesis. Along these lines the generation of a 140-member single compound DHPM library by combination of 25 aldehydes, 6 ureas/thioureas, and 7 acetoacetates or acetoamides under standard reaction conditions has been reported [123, 124]. More rapid approaches make use of microwave-enhanced solution-phase protocols [88, 89, 125]. Apart from these conventional solution-phase methods, it is also possible to employ polymer-supported reagents to aid in the purification and workup protocol. Polymer-assisted solution-phase chemistry using polymer-supported... 

It is important to emphasize the importance of chromatography for separating biological interferents from analytes of interest (Snyder and Kirkland, 1979). The valuable role for on-line purification and separation in conjunction with mass spectrometry was recognized early by Johnson and Yost (1985) and Henion and Covey (1986), and are still emphasized in the LC/MS methods used today. Many of these important chromatography features are described in Chapter 6. 

The norms for medicinal production are particularly stringent. Biological products are composed of complex molecules, produced by cell lines with a relatively recent history, and difficult to characterize. Tests performed only on the final product do not guarantee consistency of production. The purification procedures should be planned and validated for the removal of potential contaminants from diverse sources cells, culture media, equipment, and reagents used in the purification or even degradation products derived from the protein itself. There are examples of products with unexpected risks that have caused serious problems such as blood contamination by HIV-1 virus between 1980 and 1985 (Bloom, 1984) or the presence of residual infectious viruses in the poliomyelitis vaccine due to inefficient inactivation (Lubiniecki et al., 1990). 

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