Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts

A method of preparing a crystalline form of a salt of a β-turn peptidomimetic cyclic compound of formula (I)

• wherein:
• R1 is hydrogen, C1 to C6 alkyl, aryl, or an amino acid side chain substituent of a natural or unnatural amino acid;
• R3 is 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;
• Y is selected from the group consisting of hydrogen, —NO2, —COOR14, —OC(R14)3, —SO3R14, and —SO2R14;
• R5, R6, R7, R8, and R9 are independently hydrogen or C1 to C6 alkyl;
• R10 is hydrogen, methyl, t-butyl, or a protecting group;
• and
• each R14 is hydrogen, alkyl or aryl;
• X is selected from the group consisting of O, NR9, S, P, Se, C1 to C6 alkylene, SO, SO2, and NH;
• n is 0, 1, 2, 3, 4 or 5:
• the method comprising steps of:
• (a) providing a protected linear peptidomimetic compound of formula (IV)
• wherein:
• R4, R5, R6, R7, R8, R10, X, Y, and n have the meanings defined above;
• R11 and R13 are independently hydrogen or a protecting group, and at least one of R11 and R13 is a protecting group;
• R12 is 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;
• and
• Z is selected from the group consisting of IF, Cl, Br and I;
• (b) selectively deprotecting the compound of formula (IV) to form a partially protected linear peptidomimetic compound of formula (III)
• wherein:
• R2, R4, R5, R6, R7, R8, R10, R11, R13, W1, W3, X, Y, Z, and n have the meanings defined above:
• (c) cyclizing the partially protected linear peptidomimetic compound of formula (III) to form a compound of formula (II) by an intramolecular aromatic nucleophilic substitution reaction
• wherein:
• R2, R4, R5, R6, R7, R8, R10, R11, R13, W1, W3, X, Y, and n have the meanings defined above;
• (d) deprotecting all amino acid side chain protecting groups in the compound of formula (II) to obtain the salt of the β-turn peptidomimetic cyclic compound of formula (I);
• and
• (e) crystallizing the salt of the β-turn peptidomimetic cyclic compound of formula (I) to obtain the salt of the β-turn peptidomimetic cyclic compound of formula (I) in crystalline form;
• wherein the crystallizing comprises contacting the salt of the β-turn peptidomimetic cyclic compound of formula (I) with a basic solution having a basic pH, and reducing the pH to obtain an acidic pH to crystallize the salt of the β-turn peptidomimetic cyclic compound of formula (I).