Solution-phase synthesis extractions

Solution-phase synthesis [5] often needs purification or clean-up procedures after each reaction step to remove excess reagent. These methods include scavenging, extractions and associated plate transfers. All these procedures cause the loss of the desired compound. Although the purity can be improved after treatment, the chemical yield is seriously compromised. In contrast, SPOS has a unique advantage in purifying bound compound without losing compound mass. However, if the reaction is not complete at each step, the side products will form on resin and they cannot be removed while bound to the resin. The final yield and purity wiU both suffer as a result. A 90% yield for a four-step synthesis wiU produce the final product in a disappointing 65% yield. 

Chemically functionalized polymers have also been used in polymer-assisted solution-phase synthesis to perform reaction-quenching functions. These polymers often are used in operations that substitute for traditional liquid-phase extractions in classical synthesis. 

Bifunctionally tagged Mitsunobu reagents 21 and 22, quaternary ammonium carbonate resin 65, tetrafluorophthalic anhydride (as a solution-phase linking reagent), and amine-functionalized resin 2 were used in a three-step solution-phase synthesis of a series of substituted hydroxypiperidines.39 No further purification (e.g., liquid-phase extraction or chromatography) was required, and products were isolated in good yields and purities. 

In this chapter we discuss the new speeding-up techniques, optimized during the last decade, such as solid-phase extraction, polymer-assisted solution-phase synthesis, microwave-assisted organic synthesis, and flow chemistry. The improvements obtained with these techniques are not limited to a subset of chemical reactions (e.g., the reported examples), but they are fully applicable to the entire set of chemistry involved in the synthetic drug discovery process. 

Because no separation is used, only crude information about the purity of the compounds can be obtained. For example, if unreacted, synthetic starting materials (Fig. 10b) are present in a sample of a combinatorial product (Fig. 10a), these can show up in the mass spectrum of the crude product (Fig. 10c). Because the starting materials are often structurally different from the finished product, a simple extraction can be used after the synthesis to remove much of the unused reactants and obtain a cleaner mass spectrum (Fig. lOd) for a solution-phase product. Conversely, washing the resin after solid-phase synthesis or using a scavenger resin in a solution-phase synthesis can also yield improved purity by removing these excess reactants. When direct flow injection is used to characterize combinatorial libraries, it is best to avoid dimethyl sulfoxide (DMSO) as a solvent, because it interferes with reliable ionization of the analytes. 

The purity of the intermediates was assessed by TLC, MS, and H NMR, and intermediates that were less than 90% pure were not used in subsequent reactions. Unfortunately, only a randomly chosen fraction (-5%) of the final products was analyzed by MS and only a few products were analyzed by HPLC. Thus, there are no rehable data about the identities and purities of the final products. Nevertheless, this work is an impressive example of solution-phase synthesis of a large combinatorial library and an automated liquid-liquid extraction purification strategy-... 

For the parallel synthesis of ureas based on amino acids, a solid-phase synthesis as well as a solution-phase synthesis were used (Scheme 5) [11]. Solution-phase synthesis gave the desired compounds 21 in yields ranging from 80-100% and purities in the range 71-97%. The work-up involved extraction of the benzotriazole formed in the coupling steps. An aqueous borax buffer (pH 9.2) was used and the separation of the CH2CI2 layer from the aqueous phase was performed in cartridges equipped with a PTFE frit. 

Thus, products capable of forming ions can be purified by ion-exchange sohd-phase extraction in automated solution-phase synthesis. Another possible means of purifying a combinatorial solution-phase library is to selectively separate from the product those reagents, by-products, and impurities that are able to form ions by ion exchange. Both methods have appeared in the literature and a few examples are given here. 

Parallel organic synthesis can be performed both on a solid phase and in solution. Obviously, solid-phase synthesis is less difficult to automate as work-up usually consists only of simple filtration steps. Solution-phase synthesis often requires automation of work-up procedures such as liquid-liquid extraction or isolation and purification of intermediates. Strategies and devices designed for automating both solution- and solid-phase synthesis are dealt vdth in this chapter. 

This inexpensive scavenger can be prepared on a large scale and effectively eliminates excess acyl chlorides by simple aqueous extraction (Scheme 8.58). The desired compounds were isolated in high yield and purity, making this a versatile reagent for combinatorial solution-phase synthesis of amide libraries. 

Bookser, B.C. and Zhu, S., Solid phase extraction purification of carboxylic acid products from 96-well format solution phase synthesis with DOWEX 1x8-400 formate anion exchange resin, J. Comb. Chem., 3, 205, 2001. 

Scheme 8.8 Automated iterative solution-phase synthesis of oligosaccharides using fluorous solid-phase extraction (FSPE) to purify the growing oligosaccharide chain n grows by one after each coupling cycle.

While this review focuses on material that has been disclosed in the primary literature, some relevant work presented at recent meetings is included to indicate the importance of emerging technologies. This chapter covers solution phase synthesis of pools of compounds and of discrete samples and the emerging field of fluorous synthesis. The use of liquid-liquid and liquid-solid extraction has been employed in both the preparation of pools and discrete samples and will be discussed at appropriate points. 

In general, liquid/solid extraction methods offer the simplicity of solution phase synthesis and the ease of work-up by simple filtration normally offered by solid phase synthesis. As such, their use will almost certainly become much more widespread in the future. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

DIC is a moderately expensive liquid that is employed in solid-phase synthesis to avoid the obstacles presented by the use of DCC. Both the reagent and the corresponding urea are soluble in organic solvents, and hence there is no bulky precipitate to contend with. The urea cannot be removed from an organic solution by aqueous extraction however, it is soluble enough in water that final traces can be removed from a precipitated peptide by washing the latter with a water-ether mixture. Clean up of spills of DIC can cause temporary blindness if utmost care is not exercised. 

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