150250-95-6Relevant academic research and scientific papers
Highly chemoselective trichloroacetimidate-mediated alkylation of ascomycin: A convergent, practical synthesis of the immunosuppressant L- 733,725
Song, Zhiguo,DeMarco, Anthony,Zhao, Mangzhu,Corley, Edward G.,Thompson, Andrew S.,McNamara, James,Li, Yulan,Rieger, Dale,Sohar, Paul,Mathre, David J.,Tschaen, David M.,Reamer, Robert A.,Huntington, Martha F.,Ho, Guo-Jie,Tsay, Fuh-Rong,Emerson, Khateeta,Shuman, Richard,Grabowski, Edward J. J.,Reider, Paul J.
, p. 1859 - 1867 (2007/10/03)
L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy position with the imidazolyl trichloroacetimidate 16. The trichloroacetimidate-activated side chain 16 was prepared by an efficient fourstep sequence in 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergetic effects of the electron-donating protecting group on the imidazole 16, the polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimethylpivalamide mixed with acetonitrile was found to be the best solvent and trifluromethanesulfonic acid the best catalyst. This synthesis coupled with a resin column purification of L-733,725 followed by crystallization of its tartrate salt has been used to make multikilogram quantities of the bulk drug with consistent and high purity.
C32-O-imidazol-2-yl-methyl ether derivatives of the immunosuppressant ascomycin with improved therapeutic potential
Goulet, Mark T.,McAlpine, Shelli R.,Staruch, Mary Jo,Koprak, Samuel,Dumont, Francis J.,Cryan, John G.,Wiederrecht, Gregory J.,Rosa, Raymond,Wilusz, Mary Beth,Peterson, Laurence B.,Wyvratt, Matthew J.,Parsons, William H.
, p. 2253 - 2258 (2007/10/03)
A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O- cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl- methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
