The cleavage method that has predominated Boc / benzyl chemistry since introduction by Sakakibara in 19657 employs anhydrous liquid hydrogen fluoride (HF) as a cleavage reagent. This HF method gave products of higher purity and in greater yield. This method introduced an extremely hazardous operation into the peptide process, but received wide acceptance because of significant improvements in yield and purity. The HF method and other strong acidolytic cleavage procedures suffer from a common drawback that limits the process scale. This is decomposition of the cleaved peptide by the strongly acidic reaction media before the peptide product can be isolated from it. This problem can be adequately managed at small scale when small amounts of reagents are used and can be quickly removed, but for large scale processing the longer residence times that usually occur lead to reduced yields and less pure products. We present here the results of an investigation into the use of an alternate reagent for the cleavage of peptide resin that is applicable to large scale processing.

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