Liquid phase process for the preparation of GnRH peptides

摘要

A liquid phase process for preparing GnRH peptide analogs of the formula: G-AA1-(A)D-Phe-AA3-AA4-(R2)-AA5-AA6AA7-AA8-Pro-AA10-NH2 Formula 1 which comprises: (a) reacting a peptide of the formula: T-(R2)AA5-AA6-X where T is (P2)AA4 orP2 and X is AA7-OH or is -OH, with a peptide of the formula: X'-AA8-Pro-AA10-NH2 or acid-addition salt form thereof, where X' is AA7 when X is absent and X' selected from P-Ala, Gly, GABA, the D- and L- isomers of Ala, amino isobutyric acid, 6-amino-hexanoic acid, Ser, Thr, His, Tyr, Asn, and Gln' is absent when X is AA7-OH; in a liquid reaction medium in the presence of a peptide coupling reagent and a strong organic amine base to obtain a product of the formula: T-(R2)AA5-AA6-AA7-AA8-Pro-AA10-NH2 (b) removing the P2 protecting group at the N-terminus, and (c) reacting the product of step (b) or an acid addition salt thereof, with a peptide of the formula: G-AA1-(R1)D-Phe-AA3-T'or acid-addition salt form thereof, where T' is AA4-OH when T is absent and is absent when T is P2-AA4, in a liquid reaction medium to obtain a GnRH peptide of the formula: G-AA1 -(A)D-Phe-AA3-AA4-(R2)AA5-AA6-AA7-AA8-Pro-AA10-NH2.