Premium
Synthesis of highly potent lymphocyte function‐associated antigen‐1 antagonists labeled with carbon‐14 and with stable isotopes, part 3
Author(s) -
Latli Bachir,
Hrapchak Matt,
Li Guisheng,
Lorenz Jon,
Horan Josh,
Busacca Carl A.,
Senanayake Chris H.
Publication year - 2019
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3698
Subject(s) - chemistry , yield (engineering) , amine gas treating , amide , peptide bond , formate , medicinal chemistry , palladium , stereochemistry , peptide , catalysis , organic chemistry , biochemistry , materials science , metallurgy
The drug candidates ( 2 ) and ( 3 ) are highly potent LFA‐1 inhibitors. They were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor ( 5 ) and sodium formate‐ 14 C to afford acid [ 14 C]‐( 6 ), which was coupled via an amide bond to chiral amines ( 7 ) and ( 8 ) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [ 2 H 8 ]‐( 7 ) was synthesized in three steps from 2‐cyanopyridine‐ 2 H 4 using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L ‐alanine‐2,3,3,3‐ 2 H 4 ‐ N ‐ t ‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid ( 6 ) gave [ 2 H 8 ]‐( 2 ) in 36% overall yield. The amine [ 13 C 4 , 15 N]‐( 8 ) was obtained in two steps using L‐threonine‐ 14 C 4 , 15 N and then coupled to acid [ 13 C]‐( 6 ) to give [ 13 C 5 , 15 N]‐( 3 ) in 56% overall yield.