Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 115

An inconvenience can be their poor metabolic stability and oral avail-
ability. In this regard, new practical delivery technologies have been in-
vestigated such as nasal spray or micro-needles. Furthermore, chemists have
been involved in the design and synthesis of mimicking original molecules
and preparing new structures that are more resistant to degradation by
endogenous enzymes.
About 100 peptidic drugs have now reached the pharmaceutical market
and many peptides are now in the pipeline of pharmaceutical companies.
They are usually made of a 5-10 amino acid sequence but, in some cases,
larger peptides up to 50 amino acids have been synthesized and com-
mercialized. 3 One can cite as an example Fuzeon (enfuvirtide), a 36-amino-
acid antiretroviral.
As a consequence, the market for therapeutic bulk peptides is expected to
grow rapidly in the next few years. It has been evaluated as more than
$40 billion. Some of these molecules are becoming blockbusters. Indeed,
peptides such as Copaxone s (for multiple sclerosis therapy) and hormone-
related products such as leuprolide, octreotide, and goserelin (Figure 6.1)
have reached annual sales of more than $1 billion each. 4
The synthesis of peptides is now very well established with three
major approaches, in solution, in the solid phase or using recombinant
techniques for the larger peptides. The chemical preparation of these
molecules consists of assembling amino acids by stepwise successive
reactions consisting of a coupling reaction with a protected amino acid
followed by a deprotection step. The synthesis of peptides has undergone
strong developments with the discovery of solid phase supported synthesis. 5
This technique, based on the use of an insoluble polymeric support to
anchor a first amino acid, allows a stepwise synthesis, including washings to
eliminate soluble excess of coupling and deprotection reagents and side
products (Scheme 6.1). One of the major advantages is the possibility to fully
automate such a process. 6,7
Nevertheless, while being extremely practical and ecient, these methods
make use of large amounts of solvent. To produce 1 kg of peptide it is
thought that 5000 kg of solvent are needed. From this point of view, there is
a need to explore new methods for the scale up of peptide production that
would avoid or decrease the use of solvents, all the more so given that the
solvents recovered from the reaction and the washings are loaded with toxic
compounds used during the coupling or the deprotection step. 8
The building blocks that are used to make peptides are protected amino
acids. Consequently, the preparation of amino acids and their protected
derivatives are of the upmost importance in this area. Furthermore, amino
acids and their derivatives may exert biological activities on their own. 9,10
They are also important starting materials arising from the chiral pool for
the preparation of heterocycles. 11
We describe in this chapter the application of ball-milling in peptide
synthesis, including the preparation of amino acids and their protected
derivatives.