Synthesis, solution-phase

Heath J R 1992 A liquid solution phase synthesis of crystalline silicon Science 258 1131... 

The B SE group was used for intemucleotide protection and is removed with ammonia, also used to remove A -acyl protective groups. Compared with the methylsulfonylethyl group, the B SE group has better solubility properties for solution phase synthesis. ... 

In most cases, the overall synthesis time was greatly reduced (from hours or days to minutes) by switching from conventional to microwave heating, facilitating the rapid preparation of novel chemical entities. The combination of soUd-phase synthesis with microwave irradiation also allowed access to a few classes of molecules that had proven elusive via other synthetic strategies (traditional solution-phase synthesis). 

An important breakthrough in that respect was the use of soHd-phase organic synthesis (SPOS) where the attachment of the substrate to an insoluble support allowed for easy workup (filtration) and for rapid generation of products via split-mix procedures [1,2]. An important subsequent development consisted of the immobihzation of reagents, scavengers and catalysts. This technique, coined polymer-assisted solution phase chemistry (PASP), allowed solution phase synthesis of compoimds, yet still enjoying the bene-... 

Watts, P., Wiles, G., Haswell, S. J., PoMBO-ViLiAR, E., Solution phase synthesis of f-peptides using micro reactors. Tetrahedron 58, 27 (2002) 5427-5439. 

Kunz, U., Kieschning, A., A new microreactor for the solution-phase synthesis of potential drugs, in Matlosz, M., Ehefeld, W., Baselt, J. P. (Eds ), Microreaction Technology - IMRET 5 Proc. 5th Intematiorml Conference on Microreaction Technology, pp. 424 45, Springer-Verlag, Berlin (2001). 

Wen XG, Zhang WX, Yang SH (2002) Solution phase synthesis of Cu(OH)2 nanoribbons by coordination self-assembly using Cu2S nanowires as precursors. Nano Lett 2(12) 1397—1401... 

Finke, R.G. (2002) Transition-metal n anoclusters solution-phase synthesis,... 

The field of on-chip solution-phase synthesis and analysis, termed pSYN I AS (miniaturized-SYNthesis and Total Analysis Systems) is a rather new field in or-... 

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. 

Watts P, Wiles C, Haswell SJ, Pombo-ViUar E, Styring P (2001) The Synthesis of Peptides Using Microreactors. Chem Comm 11 990-991 Watts P, Wiles C, Haswell S, Pombo-Villar E (2002a) Investigation of Racemi-sation in Peptide Synthesis within a Microreactor. Lab Chip 2 141-144 Watts P, Wiles C, Haswell S, Pombo-Villar E (2002b) Solution Phase Synthesis of Beta-Peptides Using Microreactors. Tetrahedron 58 5427-5439... 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Scavenger-Based Purification of Combinatorial Libraries Generated by Solution Phase Synthesis... 

Scheme 1. Atriazine library prepared by solution phase synthesis.

Figure 2. Solution phase synthesis of the oligo(thiophene ethynylene)s by the divergent/convergent doubling approach.

Even controlled-pore glass (CPG) could be successfully employed as solid support with (9-glycosyl trichloroacetimidates as glycosyl donors. Thus, limitations of solvents and reaction temperatures in the glycosylation step, as experienced with the Merrifield resin, are restricted to those observed in solution-phase synthesis. Therefore, regio- and stereocontrol of the glycosylation reactions should be available from well-established solution-phase methodologies. 

These results demonstrate that O-glycosyl trichloroacetimidate-based oligosaccharide synthesis on solid support may eventually become a valuable alternative to solution-phase synthesis because useful experience is available for the selection of the polymer support and choice of the linker system and the glycosyl donor. Further standardization of the building blocks and the protective group pattern will finally provide the yields and the anomeric control in order to successfully plan automated syntheses of oligosaccharides also in a combinatorial manner. 

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

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