Purification open-access

Lead optimization Combinatorial/medicinal chemistry support Open access Purification Combinatorial mixtures Combinatorial libraries-quality control Taylor et al., 1995 Pullen et al., 1995 Zeng and Kassel, 1998 Zeng et al., 1998 Richmond et al., 1999 Yates et al., 2001 Dunayevskiy et al., 1995 Fang et al., 1998 Fitch 1998-1999 FIsu et al., 1999 Dulery et al., 1999 Ventura et al., 2000 Shah et al., 2000... 

Purification A variety of creative and innovative open-access LC/MS formats were developed to address throughput needs within the industrial laboratory. As the preparation of large libraries for lead discovery became routine, the burden placed on analytical techniques focused mainly on throughput and quality (Kyranos and Hogan, 1998 Van Hijfte et al., 1999). Biological assay requirements, however, normally required pure compounds. Thus, the focus shifted toward the use of automated high-throughput purification methods applied to libraries of discrete compounds (Weller, 1998-99). 

In this example the open-access system was used to determine the success of the reactions and generate a purity profile before performing automated purification u.sing HPLC (Autoprep — see Chapter 8) on the now characterised crude samples. 

Figure 13 MassLynx (Micromass UK Limited, Manchester, UK) OpenLynx open access browser data report. Plate configuration is shown in upper left. MS and UV data is displayed for the selected well position. If the requested mass is found, the well position is highlighted in green. If it is not, it is highlighted in red. Browser s of this type are also used to track fractions in mass directed auto-purification systems.

As FIA-MS and liquid chromatography mass spectrometry (LC-MS) become more pervasive in the analysis of compound libraries, open-access instrumentation is increasingly used in HTOS laboratories as well as in support of general medicinal chemistry. These open-access systems are most often used for reaction monitoring and optimization, and in some cases, for library quality control and synthesis product purification. 

Weller et al. [43] described an early high throughput UV-triggered HPLC purification system to support the parallel synthesis efforts at Bristol-Myers Squibb. This open-access instrument used fast flow rates and rapid universal reverse-phase gradient elution methods that enabled the purification of up to 200 samples per day at weights up to 200 mg/sample in an unattended mode. Customized software and hardware were developed for this system to optimize efficiency and throughput. 

Porphyrazines (pz), or tetraazaporphyrins, are compounds that can be viewed as porphyrin variants in which the meso carbon atoms are replaced with nitrogen atoms, as Fig. 1 shows (1). This difference intrinsically gives porphyrazines discrete physiochemical properties from the porphyrins. In addition, despite their similar molecular architecture, porphyrazines are prepared by an entirely different synthetic route than porphyrins—by template cyclization of maleonitrile derivatives, as in Fig. 2, where the open circle with the A in it represents the peripheral substituent of the pz—rather than by the condensation of pyrrole and aldehyde derivatives (1). The pz synthetic route allows for the preparation of macrocycles with chemical and physical properties not readily accessible to porphyrins. In particular, procedures have been developed for the synthesis of porphyrazines with S, N, or O heteroatom peripheral functionalization of the macrocycle core (2-11). It is difficult to impossible to attach the equivalent heteroatoms to the periphery of porphyrins (12). In addition, the preparation and purification of porphyrazines that bear two different kinds of substituents is readily achievable through the directed cocyclization of two different dinitriles, Fig. 3 (4, 5, 13). 

You can access the Separation, Purification and Identification CD-ROM applications through a CD-ROM Guide (Figure C.l) which is created as part of the installation process. You may open this from the Start menu, by selecting Programs followed by The Molecular World. The CD-ROM Guide has the same title as this book. 

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