Synthesis of beta-turn peptidomimetic cyclic compounds

摘要

The present invention relates to methods of preparing β-turn cyclic peptidomimetic compounds and intermediates thereof. Particularly, the present invention relates to a process for the synthesis of β-turn cyclic peptidomimetic compounds of formula I:;
where R1, R2, R3, R4, R5, R6, R7, L2, X, Y and n are as defined in the specification.
;The present invention provides a more efficient route for preparing β-turn cyclic peptidomimetic compounds and intermediates thereof.

主权项

1. A method of preparing a β-turn peptidomimetic cyclic compound of formula (I) the method comprising steps of: (a) providing a protected linear peptidomimetic compound of formula (III) (b) cyclizing the protected linear peptidomimetic compound of formula (III) to form a protected β-turn peptidomimetic cyclic compound of formula (IV) by an intramolecular aromatic nucleophilic substitution  and (c) deprotecting an amino acid side chain protecting group in the protected β-turn peptidomimetic cyclic compound of formula (IV); wherein: R1 and R3 are independently hydrogen, C1 to C6 alkyl, aryl, or an amino acid side chain substituent of a natural or unnatural amino acid; R2 and R4 are independently hydrogen or C1 to C6 alkyl, or R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; R5, R6 and R7 are independently hydrogen or C1 to C6 alkyl; Y is selected from the group consisting of hydrogen, —NO2, —COOR8, —OC(R8)3, —SO3R8, and —SO2R8; each R8 is alkyl or aryl; X is selected from the group consisting of O, N, S, P, Se, C, C1 to C6 alkylene, SO, SO2 and NH; Z is selected from the group consisting of F, Cl, Br and I; R11 and R13 are independently hydrogen or a protecting group; W1 and W3 are independently an amino acid side chain substituent of a natural or unnatural amino acid, less a hydrogen atom at the point of attachment to R11 and R13 respectively; n is 0, 1, 2, 3, 4 or 5; and L2 is H, OH, SH, COOH, NH—CH2—COOH, C1 to C6 alkyl, or C1 to C6 aryl.