title: Highly Chemoselective Trichloroacetimidate-Mediated Alkylation of Ascomycin: A Convergent, Practical Synthesis of the Immunosuppressant L-733,725.
abstract: 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.
authors.affiliation: Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Song
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authors.lastname: DeMarco
authors.forename: Mangzhu
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authors.lastname: Zhao
authors.forename: Edward G.
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authors.forename: Andrew S.
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authors.forename: James
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authors.forename: Yulan
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authors.lastname: Li
authors.forename: Dale
authors.initials: D
authors.lastname: Rieger
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authors.forename: David M.
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authors.initials: RA
authors.lastname: Reamer
authors.forename: Martha F.
authors.initials: MF
authors.lastname: Huntington
authors.forename: Guo-Jie
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authors.lastname: Ho
authors.forename: Fuh-Rong
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authors.lastname: Tsay
authors.forename: Khateeta
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authors.lastname: Emerson
authors.forename: Richard
authors.initials: R
authors.lastname: Shuman
authors.forename: Edward J. J.
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authors.lastname: Grabowski
authors.forename: Paul J.
authors.initials: PJ
authors.lastname: Reider