Purification and the Chemical Yield of Synthesis

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. 

Ideally, SPOS can be driven to completion by using the optimal reaction conditions and the excess reagent In reality, some proprietary and expensive reagents cannot be used in large excess. For kinetics or thermodynamic reasons, not all reactions can easily go to completion. Therefore, extra efforts should be made to push a reaction closer to completion. 

To determine if a solid-phase reaction is complete, on-resin analytical methods are preferable [6]. First, the quantitative or qualitative information obtained from on-resin analysis is more relevant to solid-phase reactions. Secondly, this kind of analysis is fast, direct, and without any alteration to the sample. On the other hand, analysis after cleavage would depend on the cleavage efficiency (to be discussed later) and the stability of analyte to cleavage conditions such as TFA. The 

A comparison of the amounts of resin-bound starting material and the product by cleave-and-analyze method might give a clue on the reaction completion. However, uncertainty will arise because (1) the resin-bound starting material and the product are not cleaved at the same rate and efficiency (2) the decomposition may occur during the process and (3) their UV extinction coefficients are different. 

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