Overview

The synthesis of peptides in solution phase has become a well established science in the field of organic chemistry.   Well designed protecting groups, activating reagents and coupling reagents have been developed and improved during decades of research and development by renowned peptide chemists and some are still introduced nowadays to address specific difficulties in peptide chemistry.   All this classical peptide chemistry is practiced at Peptisyntha and challenged everyday in the development of new synthetic processes.   In addition, Peptisyntha is known for relying on a proprietary solution phase process which offers significant benefits over classical solution phase reactions in some cases and for some amino acids.   This specific solution phase chemistry is used as much as possible in new process developments at Peptisyntha, to benefit from the advantages summarized hereafter.

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Proprietary technology

Basic principles

The proprietary liquid phase technology used by Peptisyntha is based on the extensive use of persilylated amino acids.  The persilylation reaction consists in a short pretreatment of the amino acids which does not require any separation step.  All functional sites containing active hydrogens including functional side chains are silylated.

Persilylation of amino acids has three main effects:

• Protection of the carboxylic group
• Protection of lateral functional groups
• Reduction of basicity of the amino group, while reactivity towards activated carboxylic groups is left unchanged.

Technical advantages

Many additional technical advantages result from the use of persilylated amino acids:

• Unprotected amino acids, which are the least expensive building blocks to perform peptide synthesis, are only soluble in water and therefore are not compatible with most coupling methods.  Upon conversion to a fully silylated derivative, amino acids become highly soluble in organic solvents and traditional coupling reagents and methods can be used.
• The attenuated basicity of the amino function, together with the possibility of working in apolar solvents, leads to a reduced risk of racemization.
• Once the coupling reaction has been performed and the reaction mixture has been worked up, the trimethylsilyl groups are removed under mild conditions (through treatment with a protic solvent like water or an alcohol) and the intermediates are recovered in a minimally protected form.
• Mild conditions can be used for the final deprotection and therefore undesirable side reactions are avoided at this often critical step.  The final crude is obtained with a high level of purity, which greatly facilitates the final purification step.
• Compared to the usual solution phase processes, the technology used by Peptisyntha is characterized by a simplification of the production scheme at all stages : protection, activation, coupling and deprotection.

Cost effectiveness of the technology

• Less expensive raw materials can be used; in certain cases even bi-functional amino acids can be used instead of their expensive, differentially protected counterparts.
• Savings in terms of processing time, reagents and solvents, are a consequence of the reduction in the number of steps.
• The persilylated intermediates being highly soluble in common organic solvents, almost quantitative yields are obtained for each intermediate step.
• The high purity of the crude peptide simplifies the final purification, hence reducing significantly the volume of solvents and effluents.

Specific technology for arginine containing peptides

Another patented asset in this innovative technology allows for working with side chain unprotected arginine residues which are used and/or isolated in the form of their highly lipophilic tetraphenylborate salts.  Peptide coupling can thereby be run at high concentration with easy recovery procedures.

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