Efficient synthesis of a small molecule, nonpeptide inhibitor of LFA-1.
A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph(3)PCl(2)-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg exchange of 9 followed by addition to SO(2) in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with L-alaninamide using K(2)CO(3) as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production of 1 on a metric ton scale.
Wang
Xiao-jun
XJ
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. xiao-jun.wang@boehringer-ingelheim.com
Xu
Yibo
Y
Zhang
Li
L
Krishnamurthy
Dhileepkumar
D
Wirth
Thomas
T
Nicola
Thomas
T
Senanayake
Chris H
CH
D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry; D014508:Urea / Q000138:chemical synthesis
D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D014508:Urea