Highly Chemoselective Trichloroacetimidate-Mediated Alkylation of Ascomycin: A Convergent, Practical Synthesis of the Immunosuppressant L-733,725.
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 four-step 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 multi-kilogram quantities of the bulk drug with consistent and high purity.
Song
Zhiguo
Z
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065.
DeMarco
Anthony
A
Zhao
Mangzhu
M
Corley
Edward G.
EG
Thompson
Andrew S.
AS
McNamara
James
J
Li
Yulan
Y
Rieger
Dale
D
Sohar
Paul
P
Mathre
David J.
DJ
Tschaen
David M.
DM
Reamer
Robert A.
RA
Huntington
Martha F.
MF
Ho
Guo-Jie
GJ
Tsay
Fuh-Rong
FR
Emerson
Khateeta
K
Shuman
Richard
R
Grabowski
Edward J. J.
EJ
Reider
Paul J.
PJ