Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts
AssigneeMimetogen Pharmaceuticals, Inc.
InventorsSébastien Rocchi, Chantal Devin, Wei Tian, Martin Bohlin
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Abstract
The present disclosure relates to methods of preparing and crystallizing β-turn cyclic peptidomimetic salts of formula I: where R1, R2, R3, R4, R5, R6, R7, R8, R10, X, Y and n are as defined in the specification. The present disclosure provides a more efficient route for preparing a crystalline form of β-turn cyclic peptidomimetic compounds and salts thereof.
Claims34
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 a amino acid side chain substituent of a natural or unnatural amino acid;
- R3 is hydrogen, C1 to C6 alkyl, aryl, or a 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 R1 and R2, 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:
- R2, R4, R5, R6 R7 R8, and R10 have the meanings defined above;
- R11 and R13 are independently hydrogen or 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 F, 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, 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, Z, and n have the meanings defined above;
- (d) deprotecting an amino acid side chain protecting group 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 compound of formula (I) in crystalline form.
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A method of preparing a crystalline form of a HCl salt of a β-turn peptidomimetic cyclic compound having the following structure:
- the method comprising steps of:
- (a) providing a protected linear peptidomimetic compound of formula (4a);
- (b) selectively deprotecting the compound of formula (4a) to form a partially protected linear peptidomimetic compound of formula (3a);
- (c) cyclizing the partially protected linear peptidomimetic compound of formula (3a) to form a compound of formula (2a) by an intramolecular aromatic nucleophilic substitution reaction;
- (d) deprotecting an amino acid side chain protecting group in the compound of formula (II) to obtain HCl salt of D3;
- and
- (e) crystallizing HCl salt of D3 to obtain the HCl salt of D3 in crystalline form.
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Dependencies are inferred from the claim text.