US 12,459,903 B2
Formation of n-protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine
John J. Freeman, New Fairfield, CT (US); Adrienne Stamper, Naugatuck, CT (US); and Melissa Heitmann, Hopewell Junction, NY (US)
Assigned to Mannkind Corporation, Valencia, CA (US)
Filed by MannKind Corp, Valencia, CA (US)
Filed on Sep. 12, 2022, as Appl. No. 17/942,576.
Application 17/942,576 is a continuation of application No. 16/866,056, filed on May 4, 2020, granted, now 11,440,891.
Application 16/866,056 is a continuation of application No. 16/266,683, filed on Feb. 4, 2019, granted, now 10,640,471, issued on May 5, 2020.
Application 16/266,683 is a continuation of application No. 15/237,427, filed on Aug. 15, 2016, granted, now 10,196,366, issued on Feb. 5, 2019.
Application 15/237,427 is a continuation of application No. 14/543,464, filed on Nov. 17, 2014, granted, now 9,416,113, issued on Aug. 16, 2016.
Application 14/543,464 is a continuation of application No. 13/368,172, filed on Feb. 7, 2012, granted, now 8,912,328, issued on Dec. 16, 2014.
Claims priority of provisional application 61/441,525, filed on Feb. 10, 2011.
Prior Publication US 2023/0034201 A1, Feb. 2, 2023
Int. Cl. C07D 241/08 (2006.01); B01J 31/02 (2006.01)
CPC C07D 241/08 (2013.01) [B01J 31/0225 (2013.01); B01J 31/0258 (2013.01); B01J 31/0259 (2013.01); B01J 2231/40 (2013.01)] 19 Claims
 
1. A method of synthesizing an oral delivery system comprising a diketopiperazine according to Formula I

OG Complex Work Unit Chemistry
the method comprising:
heating a N-protected amino acid to a temperature of 110° C. to 175° C. in the presence of a catalyst in an organic solvent;
cooling the resulting mixture by 10° C. to 75° C.;
quenching the mixture with additional cooling;
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.