Synthetic libraries, purity

The above-mentioned synthetic methods, either in solution or as solid-state protocols, have put additional pressure on the fast characterization and screening of materials libraries. The latter subject has been approached by various groups, and several high-technology methods have been reported. They will be briefly presented and discussed via several examples in this section. As of today, structural characterization of library individuals is still troublesome, nongeneralizable, and time consuming. Moreover, it has often proven to be essential to evaluate the quahty of a hbrary, and thus this process cannot be avoided. The tendency is to fuUy characterize a few library members and to assume that their composition and adherence to the planned composite in that library portion are indicative of the whole library purity and quality. 

In addition to quality control over compound collections, the issue of purity of synthetic libraries derived using combinatorial chemistry quickly came under the microscope. In the early to mid-1990s, combichem became a household word throughout the pharmaceutical industry and was believed to be a key technology that would revolutionize drug discovery. The basis of... 

Both PASP and MAOS are by now recognized as powerful tools by synthetic chemists. The use of both techniques together is somewhat newer and has not yet reached widespread use, as the relatively small number of publications testifies. However, we feel that the examples presented clearly demonstrate how powerful this combination can be, in particular if we keep in mind how complementary these tools are, one simplifying work-up and purification procedures while the other one decreases the reaction time. Considering the ever-increasing interest in the pharmaceutical industry for focused, mediumsized, high purity combinatorial libraries, this combination should attract more and more interest from both academic and industrial laboratories. At the same time, the need to increase productivity should bring synthetic and... 

The combinatorial library synthesis of a diverse set of trisubstituted ureas has been described [64]. The synthetic pathway involves the prehminary preparation of various nitrophenylcarbamates from commercially available nitrophenyl chlorofor-mate and a selection of amines allowing for wide scope in the divergence of the final urea products. In a further reaction of the nitrophenylcarbamates with a second amine, the urea was generated. Simultaneous addition of an electrophilic and basic scavenger resin removed all by-products, again allowing rapid isolation of the products in excellent yield and purity (Scheme 2.43). 

In a soluble polymer strategy comparable to resin-capture [145], Janda reported a MeO-PEGsooo-supported dialkyl borane reagent (31) that was used in the purification of a solution-phase library of y9-amino alcohols [146]. Purification was achieved by simply adding (31) to the crude reaction mixture followed by subsequent precipitation of the polymer with diethyl ether to give polymer-supported 1,3,2-oxazaboroU-dine (32) (Scheme 5.2). The /9-amino alcohol product could then be released from the soluble support by treatment with acid. In a two-step synthetic strategy that is readily amendable to automation, the isolation of a small library of /9-amino alcohols was accomplished with all compounds obtained in >80% purity. 

Relative purity measurement and the relative purity-based reaction optimization have long been used in combinatorial synthesis. In order to make high-through-put purification a success, the yield-based optimization is essential. Chemiluminescent nitrogen detection (CLND) [4] with HPLC determines the quantitative yield after each reaction step during the library feasibility and rehearsal stages. The yield of each synthetic step provides guidance for the final library synthesis. 

Polymer-assisted methodology has been used several times for parallel-array synthesis of libraries involving three to five synthetic steps. Scheme 11 shows a three-step solution-phase synthesis of 2-thioxo-4-dihydro-pyrimid-inones wherein the key purification step involved amine resin 1 to sequester excess aldehydes and isot,hiocyanates from upstream transformations. Thermal cyclization of the purified intermediates gave the desired 2-thioxo-4-dihydropyrimidinones in excellent yields and purities.83... 

It became obvious that optimization of the Rl and R2 monomer combinations (that lead to high-purity resin-bound intermediate 4) would give the best chance for eventual product formation. Most commercially available aromatic and some aliphatic aldehydes work well in the synthetic scheme. Some examples of the Rl monomers used for subsequent library formation are shown in Fig. 3. 

This section described the successful development and implementation of a traceless synthetic route to create libraries of chemically diverse benzimidazole compounds. The chemical route delivers compounds in moderate yields but in high purity directly after cleavage from the solid support. The basic concept of this traceless approach has been applied to several other related heterocyclic systems that will be reported in due... 

The 1,2,4-triazine core is a synthetically important scaffold because it could be readily transformed into a range of different heterocyclic systems such as pyridines (Sect. 3.1) via intramolecular Diels-Alder reactions with acetylenes. 1,2,4-Triazines have been synthesized by the condensation of 1,2-diketones with acid hydrazides in the presence of NH4OH in acetic acid for up to 24 h at reflux temperature. Microwave dielectric heating in closed vessels allowed the reaction to be performed at 180 °C (60 °C above the boiling point of acetic acid). As a result, the reaction time was reduced to merely 5 minutes. Subsequently, a 48-membered library of 1,2,4-triazines was generated from diverse acyl hydrazides and a-diketones [139]. Two thirds of the desired heterocycles precipitated from the reaction mixture upon cooling with > 75% purity, while the remaining part of the library was purified by preparative LCMS (Scheme 56). 

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