Chemistry Reference
In-Depth Information
process; and (b) the high cost and limited commercial availability of cata-
lysts in large quantities. An additional consideration is that some of these
catalysts are patent protected and would require substantial licensing fees
for use in a commercial route. The situation changed when, in 2005, the
process group at Boehringer Ingelheim reported the first pilot-plant imple-
mentation of an RCM reaction for the manufacture of hundreds of kilo-
grams of API.
121a
After this seminal publication, other process groups in
pharmaceutical companies embarked on similar approaches to large-sized
rings, especially in the active area of HCV protease inhibitors, such as the
examples shown below. Olefin metathesis
122
and also the green aspects
123
of
this transformation have been reviewed.
Kong and co-workers at Merck recently reported the synthesis of vani-
previr (57, MK-7009), a potent hepatitis C virus NS3/4a protease inhibitor
(Scheme 15.19), which employs RCM as the key step to generate the
macrocyclic portion of the molecule.
121g
An earlier report also by the process
group at Merck described the preparation of the macrocycle that employed a
macrolactamization approach.
80v
The researchers investigated the three
possible options to assemble the macrocycle via RCM (Scheme 15.20). Thus,
the conversion of diene 91 into RCM product 90 had been investigated
previously
80v
but it was abandoned owing to the requirements for a high
catalyst loading (Neolyst M1, 0.3 equiv.; Zhan 1B, 0.1 equiv.) and high di-
lution (
o
3 mM) to obtain an acceptable yield. Since the preparation of diene
87 was considered to be more straightforward than that of 93, the RCM of
the allyl-allyl substrate 87 was further investigated.
O
O
2nd-Generation
Grubbs-Hoveyda catalyst
94
(0.2 mol%)
2,6-dichloroquinone (10 mol%)
PhMe (13.5 mL/g
87
,0.13M)
100ºC,2h
N
N
O
O
OMe
OMe
N
H
N
N
H
N
O
O
O
O
O
O
91%
O
O
Simultaneous, slow addition of
87
and catalyst over 1 hour ,
then an additional h at 100 º C.
Nitrogen gas bubbling t hrough the reaction
mixture d uring add ition of
88
(86.4 g)
Telescoped as
PhMe solution
87
87
and catalyst
O
O
O
N
N
i. H
2
(45 psi )
5% Pd/C-Shell (25 wt%)
PhMe/IPA, 24 h
ii. crystallization from
H
2
O/IPA
O
O
H
N
O
O
OMe
S
N
N
H
H
N
N
H
N
O
O
O
O
O
O
89%
O
O
89
(77.5 g)
<10 ppm Ru
<10 ppm Pd
57
vaniprevir (MK-7009)
Scheme 15.19
Synthesis of saturated intermediate 89 via RCM en route to
vaniprevir.
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