# US 11,078,234 B2 · Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts

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- Number: US 11,078,234 B2
- Document ID: US11078234B2
- Status: Granted
- Kind: B2
- Application number: 16/184,485
- Filed: 2018-11-08
- Published: 2019-06-27
- Granted: 2021-08-03
- Earliest claimed: 2015-07-09
- Assignees: Mimetogen Pharmaceuticals, Inc.
- Applicants: Mimetogen Pharmaceuticals, Inc.
- Inventors: Sébastien Rocchi; Chantal Devin; Wei Tian; Martin Bohlin
- Web page: https://patentgrep.com/patent/US11078234B2

## CPC

- C07K 5/1021: {with the first amino acid being acidic}
- C07K 1/02: in solution {(C07K1/003, C07K1/006 take precedence)}
- C07K 1/306: {by crystallization}
- C07K 5/10: Tetrapeptides
- C07K 5/1027: {containing heteroatoms different from O, S, or N}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## 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.

## Claims

### Claim 1

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).

### Claim 2 (depends on 1)

The method of claim 1 wherein the β-turn peptidomimetic cyclic compound of formula (I) has a macrocyclic ring of from 14 to 16 ring atoms.

### Claim 3 (depends on 1)

The method of claim 1 wherein R1 and R3 are independently a side chain substituent of two different amino acids.

### Claim 4 (depends on 3)

The method of claim 3 wherein R1 and R3 are independently a side chain substituent of lysine, glutamic acid, tyrosine, isoleucine, asparagine, arginine or threonine.

### Claim 5 (depends on 1)

The method of claim 1 wherein R1 and R3 are independently a side chain substitutent of glutamic acid, lysine, isoleucine or arginine.

### Claim 6 (depends on 1)

The method of claim 1 wherein R11 and R13 are independently selected from the group consisting of trifluoroacetyl, formyl, acetyl, t-butyloxycarbonyl (BOC), cyclohexyloxycarbonyl, fluorenyl-9-methoxy-carbonyl (Fmoc), benzyloxycarbonyl (Cbz), Cbz derivatives, triphenyl, methyl, benzyl, allyloxycarbonyl, tert-butyl, alkyl silane and allyl.

### Claim 7 (depends on 1)

The method of claim 1 wherein R12 is trityl or tert-butyldimethylsilane (TBDMS).

### Claim 8 (depends on 1)

The method of claim 1 wherein W1 and W3 are independently a side chain substituent of lysine, glutamic acid, tyrosine, isoleucine, asparagine, arginine or threonine, less a hydrogen atom on the functional group.

### Claim 9 (depends on 1)

The method of claim 1 wherein X is O, S or NH.

### Claim 10 (depends on 1)

The method of claim 1 wherein Y is —NO2.

### Claim 11 (depends on 1)

The method of claim 1 wherein the cyclizing is performed in the presence of a base comprising t-BuOK, CsCO3, K2CO3, or mixtures thereof, further wherein the cyclizing is performed in a polar aprotic solvent comprises acetonitrile, tetrahydrofuran, dioxanes, or mixtures thereof.

### Claim 12 (depends on 1)

The method of claim 1 wherein the cyclizing is performed in less than about 0.5% by volume of water and less than about 0.5% by volume of methanol.

### Claim 13 (depends on 1)

The method of claim 1 wherein the cyclizing is performed at a concentration lower than 0.05M of the partially protected linear peptidomimetic intermediate (III).

### Claim 14 (depends on 1)

The method of claim 1 wherein the cyclizing is performed at a temperature of from −20° C. to 15° C.

### Claim 15 (depends on 1)

The method of claim 1 wherein the salt is a HCl salt.

### Claim 16 (depends on 1)

The method of claim 1 wherein the basic pH is from about 8 to about 12.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the pH is reduced by admixing the solution having basic pH with an acid to obtain an acidified solution.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the acidic pH is from about 0 to about 4.

### Claim 19 (depends on 17)

The method according to claim 17, wherein the admixing the solution is performed at a temperature of from about 0° C. to about 60° C.

### Claim 20

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 the amino acid side chain protecting groups in the compound of formula (2a) to obtain HCl salt of D3; and
(e) crystallizing HCl salt of D3 to obtain the HCl salt of D3 in crystalline form;
wherein the crystallizing comprises contacting HCl salt of D3 with a basic solution having a basic pH, and reducing the pH to obtain an acidic pH to precipitate or crystallize HCl salt of D3.

### Claim 21 (depends on 20)

The method of claim 20 further comprises a step of deprotecting the compound of formula (2a) by suspending the compound in a mixture of a HCl solution and acetonitrile.