This invention relates to the synthesis of peptides and in particular to solid-phase synthesis employing an insoluble resin. More specifically, the present invention provides peptide chains useful in the treatment of hormone deficiencies of the human body, such as human parathyroid hormone (hPTH), its amino-terminal 1-34 sequence, and analogs thereof, via an improved process which produces the peptide chains of interest in significantly higher yields.
U.S. Pat. No. 4,105,602 describes a solid-phase process for synthesizing hPTH using an insoluble polystyrene resin. The resin is chloromethylated at a number of sites to form a reactive resin product of the formula R--CH.sub.2 Cl where R is the resin. Phenylalanine having a protective group such as tertiarybutyloxycarbonyl (BOC), amyloxycarbonyl (AMOC) or orthonitrophenylsulfenyl (NPS) on the .alpha.-amino group is reacted with the resin to form R--CH.sub.2 --O--Phe--X where Phe is the phenylalanine residue and X is the amino-protecting group, and the phenylalanine residue is deprotected by removal of the amino-protecting group X. Successive amino acids, each having a suitable protecting group on the .alpha.-amino group, are coupled to the preceding amino acid residue on the growing resin-peptide chain by amide formation; each newly added amino acid is deprotected prior to addition of the next amino acid. When the desired peptide chain has been assembled, it is cleaved from the resin by reaction with HF.
In the aforementioned patent, trifluoroacetic acid (TFA) is illustrated exclusively as the reagent used to deprotect the phenylalanine and all other amino acid residues following attachment of the protected amino acids to the peptide chain. Indeed, TFA has for a number of years been a widely accepted reagent of choice for deprotection in all related peptide synthesis. The patent also mentions hydrochloric acid as a suitable deprotecting reagent, and hydrochloric acid in dioxane has been disclosed in a deprotecting process (Stewart & Young, Solid Phase Peptide Synthesis, 1st Ed., Freeman Pub. Co., 1969, pp. 38-39). Hydrochloric acid in glacial acetic acid is also disclosed in U.S. Pat. No. 3,891,614, as a deprotecting agent in the synthesis of calcitonin.
USPTO Backgrounds
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