A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302

Article abstract of DOI:10.1021/ol303498m

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated S_NAr reaction.

Full text of DOI:10.1021/ol303498m

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1016–1019
A Highly Convergent and Efficient
Synthesis of a Macrocyclic Hepatitis C
Virus Protease Inhibitor BI 201302
Xudong Wei,* Chutian Shu,† Nizar Haddad, Xingzhong Zeng, Nitinchandra D. Patel,
Zhulin Tan, Jianxiu Liu, Heewon Lee, Sherry Shen, Scot Campbell, Richard J. Varsolona,
Carl A. Busacca, Azad Hossain, Nathan K. Yee, and Chris H. Senanayake
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, 900 Ridgebury Road,
Ridgefield, Connecticut 06877, United States
xudong.wei@boehringer-ingeheim.com
Received December 21, 2012
ABSTRACT
A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved,
in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1À0.2 M
concentration) and the efficient sulfone-mediated SNAr reaction.
Over the past two decades substantial development has
been made in novel chemotherapies for chronic type C
hepatitis, which aimed to change the dire prognosis of
infected patients.1 In 2002, the first human proof-of-
concept for a direct acting antihepatitis C virus (HCV)
drug was achieved with the Boehringer-Ingelheim NS3
protease inhibitor Ciluprevir (BILN2061, 1, Figue 1).2
Recently, two anti-HCV drugs were approved by the
FDA to treat HCV infected patients.3,4
The emerging HCV protease inhibitors not only ex-
emplified the power of modern synthetic methods in drug
discovery but also posed unique challenges for the devel-
opment of practical and economical large scale syntheses
to support clinical trials and potential market demands.
As our continued effort in this area,5 herein we report a
highly convergent and efficient synthesis of the macro-
cyclic HCV protease inhibitor BI 201302 (2).
Our new synthetic strategy (Scheme 1) focuses on
tackling several unmet but critical challenges encountered
in our initial scale-up work of BILN 2061.5 At first, the
required high dilution (0.01 M) of the ring-closing
† Current address: Xuanzhu Pharmaceuticals, Inc., 2518 Tianchen Street,
Jinan, Shandong, 250101, China.
(1) Chen, K. X.;Njoroge, F. G. Curr. Opin. Invest. Drugs 2009, 10, 821.
(2) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger,
G.; Bonneau, P.; Boes, M.; Cameron, D. R.; Cartier, M.; Cordingley,
M. G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.;
ꢀ
Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.;
Sentjens, R. E.; St. George, R.; Simoneau, B.; Steinmann, G.; Thibeault,
ꢁ
D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llinas-Brunet, M.
(5) (a) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos,
R. P.; Gallou, F.; Wang, X-j.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs,
V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.;
Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.;
Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org. Chem. 2006, 71,
7133. (b) Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process
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(3) Boceprevir/Victrelis was approved by US FDA on May 13th 2011.
(4) Telaprevir/Incivek was approved by US FDA on May 23rd 2011.
r
10.1021/ol303498m
Published on Web 02/13/2013
2013 American Chemical Society

Scheme 1. Retrosynthetic Strategy for BI 201302
Figure 1. Macrocyclic HCV inhibitors.
metathesis (RCM) reaction must be overcome, which is a
typical problem for macrocyclization. The high ruthe-
nium (Ru) catalyst loading (3À5 mol %) for RCM
reaction was impractical due to not only its high cost
but also the extreme difficulty of removing high levels
of residual Ru metal from the Active Pharmaceutical
Ingredient (API). Its long reaction time (∼24 h) and risk
for epimerization6 were also troublesome for production.
Second, the assembly sequence via double SN2 reactions
was lengthy and costly, and a higher level of the assembly
convergency called for a direct installation of the quino-
line heterocycle to the macrocycle through an SNAr reac-
tion to avoid the double inversions of the stereocenter at
the C-4 position of the hydroxyproline moiety (4).
The development of a more efficient RCM started from
various initial observations on our early RCM process.
It was noticed that the remote substituent at the C-4 posi-
tion of the hydroxyproline moiety in 4 had a small but
detectable effect5 on the RCM rate and therefore on the
Effective Molarity7 (EM = kintra/kinter). This small effect
was tentatively ascribed to subtle conformational factors.
Also, when the initiation of the reaction was monitored
using a substoichiometric amount of Grubbs’ catalyst
(7, Scheme 2), carbene transfer occurred to a large extent
(96%) at the vinylcyclopropane moiety 8, where the Ru
may be stabilized by chelation to the carbonyl group.
Such stabilization, in turn, may reduce the concentration
of the active Ru catalyst in the reaction and negatively
affect the rate of the RCM reaction.6 Guided by these
observations, we postulated that substitution on the NH
of the P1 amide (vinylcyclopropane amimo acid unit)
would change such coordinative stabilization and its
conformation in which the Ru-insertion pathway would
be altered. A number of derivatives were subsequently
prepared, in which the amide bond was protected with
various removable groups.8,9
profound effects on the efficiency of the RCM reaction.
As shown in Scheme 2, the simple N-Boc substrate 6 not
only switches the initiation site of the RCM reaction
through interrupting the coordinative stabilization by
the ester group but also dramatically increase its effective
molarity which enables the RCM reaction to be per-
formed at much higher concentrations. As a result, in
comparison with the corresponding NÀH substrate 5 the
desired RCM reaction proceeded 3À4 times faster, and
more importantly it could be carried out at a 10À20-fold
greater concentration (0.1À0.2 M) which was unprece-
dented for this type of macrocyclization. In consideration
of the reversible nature of the metathesis reaction, the
origins of this “N-Boc effect” seem to be grounded in
favorable kinetic and thermodynamic effects. The strate-
gic induction of an electron-withdrawing group on the
RCM linker can direct the initiation site and have a
remarkable effect on the RCM, hence complementing
the known relay strategy;10,11 also it increases the thermo-
dynamic EM, presumably by reducing the ring strain of
the macrocyclic product because of its favored conforma-
tional characteristics. This hypothesis is supported by
theoretical analysis9,12 through the calculation of the con-
formational energy change of the macrocycle between the
open chain molecules with and without Boc substitution.
With the critical RCM obstacle resolved, the synthesis
of BI 201302 used similar building blocks developed for
BILN 2061.5a,13 For preparation of the RCM precursor,
(S)-2-(tert-butyloxycarbonyl)-amino-8-nonenoic acid (12)
was first coupled with trans-hydroxyl-proline ester (13)
(10) Change of initiation site is known to affect RCM. See: Wallace,
D. Angew. Chem., Int. Ed. 2005, 44, 1912–1915.
(11) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,
H. J. Am. Chem. Soc. 2004, 126, 10210–10211.
As reported in our preliminary studies, the modifica-
tions of the RCM substrates 6, through introducing
a substituent on the NH of the P1 amide, led to the
€
(12) Jaguar, v 6.5; Schrodinger, Inc.: New York, 2006.
(13) (a) Beaulieu, P. L.; Gillard, J.; Bailey, M. D.; Boucher, C.;
Ducepee, J.-S.; Simoneau, B.; Wang, X.-J.; Zhang, L.; Grozinger, K.;
Houpis, I.; Farina, V.; Heimroth, H.; Krueger, T.; Schnaubelt, J. J. Org.
Chem. 2005, 70, 5869–5879. (b) Faucher, A.-M.; Bailey, M. D.; Beaulieu,
P. L.; Brochu, C.; Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.;
Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.;
(6) Zeng, X.; Wei, X.; Farina, V.; Napolitano, E.; Xu, Y.; Zhang, L.;
Haddad, N.; Yee, N. K.; Grinberg, N.; Shen, S.; Senanayake, C. H.
J. Org. Chem. 2006, 71, 8864.
(7) Mitchell, L.; Parkinson, J. A.; Percy, J. M.; Singh, K. J. Org.
Chem. 2008, 73, 2389–2395.
(8) Shu, C. (2007). PCT Int. Appl. WO 2007030656.
(9) Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca,
C. A.; Han, Z.; Farina, V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303.
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Llinas-Brunet, M. Org. Lett. 2004, 6 (17), 2901–2904. (c) Wang, X.-j.;
Zhang, L.; Smith-Keenan, L. L.; Houpis, I. N.; Farina, V. Org. Process
Res. Dev. 2007, 11, 60–63. (d) Frutos, R. P.; Haddad, N.; Houpis, I. N.;
Johnson, M.; Smith-Keenan, L. L.; Fuchs, V.; Yee, N. K.; Farina, V.;
Faucher, A-M; Brochu, C.; Hache, B.; Duceppe, J.-S.; Beaulieu, P.
Synthesis 2006, 15, 2563–2567.
Org. Lett., Vol. 15, No. 5, 2013
1017

Scheme 2. Ring-Closing Metathesis of 5/6
directly using cyanuric chloride as a reagent (Scheme 3).
After hydrolysis, the crystalline dipeptide 14 was activated
as the mixed anhydride and reacted with the vinylcyclo-
propane amino acid unit 15 to furnish an unprotected
hydroxy tripeptide diene 16.
Scheme 3. Synthesis of BI 201302
A streamlined one-pot preparation of RCM precursor
6 from 16 was then developed, the hydroxyl group of
crude intermediate 16 was acetylated with acetic anhy-
dride, and the amide-NH was protected with Boc2O using
DMAP as the catalyst. The tripeptide diene 6 was ob-
tained as a highly crystalline white solid (>99% purity)
in 81% overall yield from intermediate 16, in which the
high purity of this diene precursor 6 undoubtedly enabled
a very robust RCM process. When a solution of 6
(0.1 M in toluene) was heated to reflux and a solution
of Grela catalyst14 (17) (0.1 mol %) was added in por-
tions, the RCM reaction was instantaneously initiated
with the immediate release of ethylene gas and completed
once all of the catalyst was added to furnish the desired
RCM product 11 in excellent 93% assay yield. Again, in
the same pot, the crude RCM product 11 was treated
with methanesulfonic acid followed by NaOH to se-
quentially deprotect the Boc group, acetyl group, and
ester; the desired hydroxyl acid intermediate 4 was
obtained as a highly crystalline solid (75% yield in
two steps) in >99% purity.
When 4 was subjected to various SNAr reaction condi-
tions with the bromochloroquinoline 1915 (Scheme 4), a
sluggish reaction (<40% assay yield) was typically ob-
tained regardless of the bases used (t-BuOK, KHMDS,
or NaH). Such a low yield was obviously unacceptable
for the final synthetic step of the targeted molecule.
Similar observations were also reported by others in
literature.16
its leaving group effect. It appeared to us that sulfonyl
substituted pyridines and quinolines are known substrates
for SNAr reactions,17 although synthetic applications18
were quite limited possibly due to the lack of an easy access
In order to improve this SNAr reaction, we investigated
the reactivity of the quinoline electrophile by evaluating
(14) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.;
Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318.
(15) The bromochloroquinoline fragment 19 was synthesized by a
similar approach used for BILN2061.13d
(17) (a) Illuminati, G. Adv. Heterocycl. Chem. 1965, 4, 145. (b) Barlin,
G. B.; Brown, W. V. J. Chem. Soc. (B) 1967, 648. (c) Barlin, G. B.;
Brown, W. V. J. Chem. Soc. (B) 1967, 736.
(16) Campbell, J. A.; Good, A. C. Patent WO03/053349.
1018
Org. Lett., Vol. 15, No. 5, 2013

react with PhSO2Na similarly which would avoid the use
of an excess amount of corrosive reagent POCl3. How-
ever, initial experiments failed until a critical observation
was made in which a small amount of protic acid could
greatly accelerate the reaction rate possibly via a more
reactive pyridinium species. Thus, a facile alternative
synthesis of 18 via a tosylate intermediate was developed
as shown in Scheme 5. At first t-BuOK promoted cycliza-
tion of 20 afforded the quinolone 21 in 89% yield, which
was then tosylated at room temperature and then treated
with PhSO2Na and 1.0 equiv of benzenesulfonic acid to
convert the tosylate 22 to sulfone 18 smoothly at 75 °C in
8 h. After a simple workup, the desired sulfone 18 was
isolated as a solid in an excellent overall yield.
Scheme 4. SNAr Reactions
to sulfonyl substituted heterocycles.19 Nevertheless, we
converted chloroquinoline 19 to the corresponding sulfone
18 by heating with PhSO2Na in DMF and then tested 18
for the desired SNAr reaction (Scheme 3). Gratifyingly,
it was found that the reaction of 18 and 4 prompted by
t-BuOK went to completion in less than 5 h with excellent
yield (91À93% by assay). We found the only significant
impurity (1À2%) was the tert-butyl carbamate analogue
of BI201302, which was obviously generated from the
trans-carbamoylation to replace the cyclopentyloxy group
by tert-butoxide. This impurity was difficult to remove
from the final API because it had very similar physico-
chemical properties. In this regard, potassium 3,7-di-
methyl-3-octylate (KDMO) was found to be a superior
reagent, because the corresponding DMO-carbamate was
much more soluble in the solvent and could be removed
easily by crystallization. Thus this final step proceeded
smoothly to produce BI201302 as a meglumine (MU) salt
in 74% isolated yield with >99% purity (single individual
impurity <0.3%).
Scheme 5. Alternative Synthesis of 18
In summary, the development of an efficient and scal-
able chemical process for a macrocyclic HCV protease
inhibitor such as BI 201302 presented unique synthetic
challenges for process chemists, particularly for the scale-
up of the RCM reaction for macrocycle formation.
During the course of these studies, a number of critical
parameters for the RCM reaction, such as the initiation
site, conformations of substrate/products, and substrate
quality, were studied which led to the successful develop-
ment of a practical process for scaling up (0.1 mol %
Ru catalyst, 0.1À0.2 M concentration). Also, the synth-
esis herein described represents the optimal convergent
strategy for the assembly of macrocyclic BI 201302 ame-
nable for its potential commercialization.
The above-mentioned highly efficient SNAr reaction
called for a more practical and environmentally benign
synthesis of the key intermediate 18. In literature sulfo-
nylquinolines are normally prepared by the reaction of
chloroquinoline with PhSO2Na at high temperature or
of chloroquinoline with a thiol to obtain the thio-ether
followed by oxidation to the sulfone.19 We envisioned
that a readily accessible tosylate 22 (Scheme 5) would
(18) (a)Armspach,D.;Constable,E.C.;Diederich,F.;Housecroft, C. E.;
Nierengarten, J.-F. Chem. Commun. 1996, 2009–2010. (b) Furukawa, N.;
Ogawa, S.; Kawai, T.; Oae, S. Tetrahedron Lett. 1983, 3243. (c) Furukawa,
N.; Ogawa, S.; Kawai, T. J. Chem. Soc., Perkin Trans. 1 1984, 1839.
(19) (a) Maloney, K. M.; Kuethe, J. T.; Linn, K. Org. Lett. 2011, 13,
102–105. (b) Trankle, W. G.; Kopach, M. E. Org. Process Res. Dev.
2007, 11, 913. (c) Bellare, R. A.; Ganapathi, K. Proc. Indian Acad. Sci. A
1951, 51, 183–186.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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