US 9,809,576 B1
Synthetic route to anti-viral agents
Russell D. Cink, Grayslake, IL (US); Kirill A. Lukin, Vernon Hills, IL (US); Marvin R. Leanna, Grayslake, IL (US); Matthew J. Pelc, Pleasant Prairie, WI (US); Timothy B. Towne, Lindenhurst, IL (US); Dennie S. Welch, Gurnee, IL (US); Kenneth M. Engstrom, Mundelein, IL (US); Matthew M. Ravn, Round Lake Beach, IL (US); Richard D. Bishop, Third Lake, IL (US); Gang Zhao, Northbrook, IL (US); Jianzhang Mei, Lake Forest, IL (US); Jeff M. Kallemeyn, Libertyville, IL (US); David R. Hill, Gurnee, IL (US); Michael J. Abrahamson, Chicago, IL (US); and Westin H. Morrill, Grayslake, IL (US)
Assigned to AbbVie Inc., North Chicago, IL (US)
Filed by AbbVie Inc., North Chicago, IL (US)
Filed on Jul. 17, 2015, as Appl. No. 14/802,372.
Claims priority of provisional application 62/026,412, filed on Jul. 18, 2014.
Int. Cl. C07D 403/12 (2006.01); C07C 69/74 (2006.01); C07D 241/44 (2006.01); C07D 405/06 (2006.01); C07C 271/34 (2006.01); C07C 67/08 (2006.01); C07D 405/14 (2006.01); C07D 487/04 (2006.01); C07C 269/06 (2006.01); C07C 269/04 (2006.01); C07C 41/26 (2006.01); C07C 43/196 (2006.01)
CPC C07D 403/12 (2013.01) [C07C 41/26 (2013.01); C07C 43/196 (2013.01); C07C 67/08 (2013.01); C07C 69/74 (2013.01); C07C 269/04 (2013.01); C07C 269/06 (2013.01); C07C 271/34 (2013.01); C07D 241/44 (2013.01); C07D 405/06 (2013.01); C07D 405/14 (2013.01); C07D 487/04 (2013.01)] 2 Claims
 
1. A method comprising one or more of steps A, C, D, E, E′, F, F′, G, G′, H, I, J, K, L, M, and N:
(A)

OG Complex Work Unit Drawing
wherein the reaction takes place in a sixteenth solvent, thereby forming a thirteenth product mixture comprising

OG Complex Work Unit Drawing
(C)

OG Complex Work Unit Drawing
wherein Step 1 of the reaction takes place in a thirteenth solvent in the presence of a seventh base; and Step 2 of the reaction takes place in a fourteenth solvent, thereby forming an eleventh product mixture comprising

OG Complex Work Unit Drawing
(D)

OG Complex Work Unit Drawing
wherein the reaction takes place in a twelfth solvent in the presence of a second acid, thereby forming a tenth product mixture comprising

OG Complex Work Unit Drawing
(E)

OG Complex Work Unit Drawing
wherein the reaction takes place in an eleventh solvent in the presence of a sixth base, thereby forming a ninth product mixture comprising

OG Complex Work Unit Drawing
(E′)

OG Complex Work Unit Drawing
wherein step (1) takes place in a nineteenth solvent in the presence of an eighth base, and step (2) takes place in a twentieth solvent in the presence of a ninth base, thereby forming a sixteenth product mixture comprising

OG Complex Work Unit Drawing
(F)

OG Complex Work Unit Drawing
wherein the reaction takes place in a tenth solvent in the presence of a fifth base, thereby forming an eighth product mixture comprising

OG Complex Work Unit Drawing
(F′)

OG Complex Work Unit Drawing
wherein the reaction takes place in a eighteenth solvent in the presence of a reagent, thereby forming an fifteenth product mixture comprising

OG Complex Work Unit Drawing
(G)

OG Complex Work Unit Drawing
wherein the reaction takes place in a ninth solvent in the presence of a fourth base, thereby forming a seventh product mixture comprising

OG Complex Work Unit Drawing
(G′)

OG Complex Work Unit Drawing
wherein the reaction takes place in a seventeenth solvent in the presence of an oxidant, thereby forming a fourteenth product mixture comprising

OG Complex Work Unit Drawing
(H)

OG Complex Work Unit Drawing
wherein the reaction takes place in an eighth solvent, thereby forming a sixth product mixture comprising

OG Complex Work Unit Drawing
(I)

OG Complex Work Unit Drawing
wherein Step 1 of the reaction takes place in a sixth solvent at a sixth temperature to effect a Claisen rearrangement, and Step 2 of the reaction takes place in a seventh solvent at a seventh temperature, thereby forming a fifth product mixture comprising

OG Complex Work Unit Drawing
(J)

OG Complex Work Unit Drawing
wherein the reaction takes place in a fifth solvent in the presence of a first acid and a hydrogen source, thereby forming a fourth product mixture comprising

OG Complex Work Unit Drawing
(K)

OG Complex Work Unit Drawing
wherein Step 1 of the reaction takes place in a third solvent in the presence of a second base; and Step 2 of the reaction takes place in a fourth solvent in the presence of a third base, thereby forming a third product mixture comprising

OG Complex Work Unit Drawing
(L)

OG Complex Work Unit Drawing
wherein the reaction takes place in a second solvent in the presence of a first enzyme, thereby forming a second product mixture comprising

OG Complex Work Unit Drawing
(M)

OG Complex Work Unit Drawing
wherein the reaction takes place in a first solvent in the presence of a first base, thereby forming a first product mixture comprising

OG Complex Work Unit Drawing
or
(N)

OG Complex Work Unit Drawing
wherein:
LG is a leaving group; and
the second reagent comprises one or more reagents sufficient to replace the OH with group LG.