Formation of N-protected bis-3,6-(4-aminoalkyl)-2,5,diketopiperazine

• US 8,912,328 B2
• Filed: 02/07/2012
• Issued: 12/16/2014
• Est. Priority Date: 02/10/2011
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Freeman, John J., Stamper, Adrienne, Heitmann, Melissa
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US13/368,172
• Publication Number:
  US 20130012710A1
• Time in Patent Office: 1,043 Days
• Field of Search: 544/385
• US Class Current: 544/385
• CPC Class Codes: 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
• CPC Class Codes: B01J 31/0225 comprising sulfonic acid groups or the corresponding salts
• CPC Class Codes: B01J 31/0258 Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
• CPC Class Codes: 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
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms

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

1. A method for the synthesis of 3,6-bis-4-(N-trifluoroacetyl)aminobutyl-2,5- diketopiperazine comprising:

heating a mixture of ε

-trifluoroacetyl-L-lysine in the presence of phosphorous pentoxide in N-methyl-2-pyrrolidone, to a temperature of between 150° and

175°

C. for between 0.25 and 5 hours, the concentration of phosphorous pentoxide is from 20% to 35% that of the lysine; and

quenching the mixture with water.

2. The method of claim 1, wherein the mixture is heated to a temperature of between 160°

and 170°

C.

3. The method of claim 1, wherein the mixture is heated for between 1 and 2 hours.

4. The method of claim 1, wherein the mixture is cooled prior to quenching.

5. The method of claim 1, wherein the mixture is heated to a temperature of between 160°

and 165°

C.

6. The method of claim 1, wherein the mixture is heated for about 1.5 hours.

7. The method of claim 1, wherein the concentration of phosphorous pentoxide is from about 20% to 30% that of the lysine.