Parallel compound synthesis

Selway, C. N. Terrett, N. K. 1996. Parallel-compound synthesis methodology for accelerating drug discovery. Bioorg. Med. Chem., 4,645-654. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation the Si-TrisAmine was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining <06MCL3777>. 

The advantages of functional polymers are best realized when used in two situations— multistep sequential reactions and automated parallel combinatorial synthesis to produce libraries of compounds. In both situations there is a large savings in the time and expense of carrying out the many chemical reactions and their corresponding handling and purification steps. 

The combination of the catalytic method and the three-phase separation could be applied to the parallel rapid synthesis of a small library of nine compounds of type 7 using the Giese reaction (eq. 5.3). The attractive prospect from this simple experiment arises from the very efficient workup protocol, allowing facile and quantitative separation even if excess reagents... 

Other 3-substituted l-lithio-l-(methoxymethoxy)allenes such as compounds 747-749 have been used in the synthesis of cyclopentenones. The intermediate 747 and an amide have been used for the synthesis of A7-10-chloro-15-deoxy PGA1 ethyl ester1079 and, by reaction with a trifluoromethyl dienone, for the synthesis of 15-deoxy-12-hydroxy-10-(trifluoromethyl)- A7 PGA1 ethyl ester1080. A combination of allenyllithiums 740, 748 and 749 with amides allowed the parallel chemical synthesis of cyclopentenones1081. 

Parallel liquid synthesis has been applied to the synthesis of a range of N,N -disubstituted 3-aminoazepin-2-ones 7 (e.g. R = w-BrC6H4) starting from 6. These compounds were required for SAR studies as specific famesyl transferase inhibitors <03BMC3193>. 

Over the last five years the number of samples submitted for analytical characterisation has increased enormously. One of the main factors affecting these sample numbers has been the rapid growth in techniques such as combinatorial chemistry [4,5], In addition to this, combinatorial approaches have also lent themselves to parallel synthesis methods where smaller numbers of distinct chemical entities are made in parallel [6]. Whilst this approach produces smaller numbers of compounds than the true combinatorial methods it still represents a significant increase in sample numbers compared to the more conventional, single compound synthesis approach of old. 

The advent of experimental techniques such as combinatorial and parallel chemical synthesis, and high-throughput screening has enabled the production of massive amounts of data. These compound databases have played a key role in drug design (Miller, 2002) and other research areas such as Agrochemistry and Food Chemistry. Current computational... 

Efficient parallel synthesis of larger numbers of single defined compounds plays an ever more important role in dmg research. While it is possible to manually synthesize mixtures of large numbers of compounds on a solid phase employing the spHt-and-mix method, in parallel single compound synthesis a number of reaction vessels equal to the number of desired final products has to be handled (at least in the final step of the synthetic sequence) [l]. This latter approach clearly benefits from, or even requires assistance of some sort of robotic equipment/ devices. 

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