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 the
third fragment which is then coupled to the second fragment and then the
first fragment in solution. Alternatively, a different second fragment is
coupled to the first fragment in the solid phase. Then, solution phase
chemistry is then used to add additional amino acid material to a
different third fragment. Subsequently, this different third fragment is
coupled to the coupled first and different second fragment 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 the other fragments. The present
invention is very useful for forming insulinotropic peptides such as
GLP-1(7-36) and its natural and non-natural counterparts.