Process and apparatus for the synthesis of peptides not linked to polymers

In a process for the synthesis of peptides by the reaction of a peptide or amino acid having a free amino group with a coupling peptide or amino acid having a protected amino group and an activated carboxyl group, wherein additional functional groups are protected, the improvement comprising conducting said synthesis in a single reactor vessel comprising the steps of charging to said vessel a non-polymerbound peptide or amino acid protected on its free amino group by a removable protecting group, adding sufficient acid to acidolytically remove the amino-protecting group from the peptide or amino acid and form a salt of said peptide or amino acid, adding to said vessel an organic solvent precipitant to form a solid precipitated peptide or amino acid salt and a liquid phase, separating the solid and removing the liquid phase from the vessel while retaining the solid peptide or amino acid in said vessel;

• dissolving or suspending said solid peptide or amino acid in a solvent suitable for an acylation reaction by adding the solvent to said vessel;
• acylating the free amino group of said peptide or amino acid by adding an organic base and an acylating peptide or amino acid having an N-protected amino group and an activated carboxyl group whereby said activated carboxyl group of the acylating peptide or amino acid reacts with the free amino group of the peptide or amino acid to couple said peptides or amino acids in said vessel;
• adding a non-solvent for the resulting coupled peptide to said vessel to precipitate the coupled peptide, and separating and removing the liquid phase from the vessel to provide the isolated solid peptide product, wherein all intermediates formed during said reactions are isolated in said reactor vessel.