The present invention relates to the preparation of insulinotropic
peptides that are synthesized using a solid and solution phase ("hybrid")
approach. Generally, the approach includes synthesizing three different
peptide intermediate fragments using solid phase chemistry. Solution
phase chemistry is then used to add additional amino acid material to one
of the fragments. The fragments are then coupled together in the solution
phase. The use of a pseudoproline in one of the fragments eases solid
phase synthesis of that fragment and also eases subsequent solution phase
coupling of this fragment to other fragments. The present invention is
very useful for forming insulinotropic peptides such as Exenatide(1-39)
and its natural and non-natural counterparts.