# US 11,440,891 B2 · Formation of N-protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine

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- Number: US 11,440,891 B2
- Document ID: US11440891B2
- Status: Granted
- Kind: B2
- Application number: 16/866,056
- Filed: 2020-05-04
- Published: 2020-08-20
- Granted: 2022-09-13
- Earliest claimed: 2011-02-10
- Assignees: MannKind Corporation
- Applicants: MannKind Corp
- Inventors: John J. Freeman; Adrienne Stamper; Melissa Heitmann
- Web page: https://patentgrep.com/patent/US11440891B2

## CPC

- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- B01J 31/0225: {comprising sulfonic acid groups or the corresponding salts}
- B01J 31/0258: {Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H}
- B01J 31/0259: {comprising phosphorous acid (-ester) groups ((RO)P(OR')2) or the isomeric phosphonic acid (-ester) groups (R(R'O)2P=O), i.e. R= C, R'= C, H}
- B01J 2231/40: Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

The disclosed embodiments detail improved methods for the synthesis of diketopiperazines from amino acids. In particular improved methods for the cyclocondensation and purification of N-protected 3,6-(aminoalkyl)-2,5-diketopiperazines from N-protected amino acids. Disclosed embodiments describe methods for the synthesis of 3,6-bis-[N-protected aminoalkyl]-2,5-diketopiperazine comprising heating a mixture of an amino acid in the presence of a catalyst in an organic solvent. The catalyst is selected from the group comprising sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid and phosphorous pentoxide among others. The solvent is selected from the group comprising: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, ethyldiglyme, m-cresol, p-cresol, o-cresol, xylenes, ethylene glycol and phenol among others.

## Claims

### Claim 1

A method for the synthesis of a diketopiperazine according to Formula I, the diketopiperazine synthesized by the method comprising
mixing a N-protected amino acid and a phosphorous-containing catalyst in an organic solvent, heating the mixture to a temperature of 110° C. to 175° C.; and quenching the mixture in a second solvent
wherein n is 0 to 3; wherein PG is selected from trifluoroacetyl, CBz, and acetyl;
wherein the catalyst is present in a concentration of 20% to 50% that of the N-protected amino acid.

### Claim 2 (depends on 1)

The method of claim 1, wherein n is equal to 3.

### Claim 3 (depends on 1)

The method of claim 1, wherein PG is trifluoroacetyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein PG is Cbz.

### Claim 5 (depends on 1)

The method of claim 1, wherein the organic solvent is N-methyl-2-pyrrolidone.

### Claim 6 (depends on 1)

The method of claim 1, wherein the N-protected amino acid is ε-trifluoroacetyl-L-lysine.

### Claim 7 (depends on 1)

The method of claim 1, wherein the catalyst is selected from phosphoric acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid and phosphorous pentoxide.

### Claim 8 (depends on 1)

The method of claim 1, wherein the mixture is heated for between 0.25 and 6 hours.

### Claim 9 (depends on 1)

The method of claim 1, wherein the N-protected amino acid is ε-Cbz-L-lysine.

### Claim 10 (depends on 1)

The method of claim 1, wherein the N-protected amino acid is γ-trifluoroacetyl-ornithine.

### Claim 11 (depends on 1)

The method of claim 1, wherein the N-protected amino acid is γ-Cbz-ornithine.

### Claim 12 (depends on 1)

The method of claim 1, wherein the catalyst is phosphorous pentoxide.

### Claim 13 (depends on 12)

The method of claim 12, wherein the concentration of phosphorous pentoxide is from 20% to 40% that of the N-protected amino acid.

### Claim 14 (depends on 12)

The method of claim 12, wherein the concentration of phosphorous pentoxide is from 20% to 35% that of the N-protected amino acid.

### Claim 15 (depends on 1)

The method of claim 1, wherein the second solvent is water.

### Claim 16 (depends on 1)

The method of claim 1, wherein the mixture is heated to a temperature of between 130° C. and 175° C.

### Claim 17 (depends on 1)

The method of claim 1, wherein the mixture is heated to a temperature of between 150° and 175° C.

### Claim 18 (depends on 1)

The method of claim 1, wherein the mixture is heated for between 0.25 and 5 hours.

### Claim 19

A method for the synthesis of a diketopiperazine according to Formula I, the diketopiperazine synthesized according to the method comprising:
heating a mixture of an N-protected amino acid of Formula II in the presence of a phosphorous catalyst in an organic solvent;
wherein PG is selected from the group consisting of trifluoroacetyl, CBz, and acetyl, and n is 0 to 3;
wherein the catalyst is present in a concentration of 20% to 35% that of the amino acid; and
wherein the solvent is selected from the group consisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme; and
wherein the mixture is heated to a temperature of between 120° and 175° C. for at least 0.25 hours.