Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis.
A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.
Yee
Nathan K
NK
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, USA. nyee@rdg.boehringer-ingelheim.com
Farina
Vittorio
V
Houpis
Ioannis N
IN
Haddad
Nizar
N
Frutos
Rogelio P
RP
Gallou
Fabrice
F
Wang
Xiao-Jun
XJ
Wei
Xudong
X
Simpson
Robert D
RD
Feng
Xuwu
X
Fuchs
Victor
V
Xu
Yibo
Y
Tan
Jonathan
J
Zhang
Li
L
Xu
Jinghua
J
Smith-Keenan
Lana L
LL
Vitous
Jana
J
Ridges
Michael D
MD
Spinelli
Earl M
EM
Johnson
Michael
M
Donsbach
Kai
K
Nicola
Thomas
T
Brenner
Michael
M
Winter
Eric
E
Kreye
Paul
P
Samstag
Wendelin
W
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; C479555:BILN 2061; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles