Fasudil (HA-1077)15 is the only marketed inhibitor of ROCK
and is used in Japan for the treatment of life-threatening cerebral
vasospasm16 after subarachnoidal bleeding.17 Other ROCK
inhibitors reported by different inventors did not reach late
clinical phases.13b,18-23
In our own research program we developed azaindole 16 as
potent and selective ROCK-1/-2 inhibitor. We recently reported
on the design and synthesis24 of 16 and on its pharmacological
characterization25 as a highly potent, selective, and orally
available antihypertensive agent. The medicinal chemistry
synthesis was designed to facilitate late-stage incorporation of
structural diversity on the azaindole hinge-binding motif. For
the preparation of 16 on multigram scale an improved synthetic
route was required. Herein, we are describing the development
of an alternative route with 10-fold improved yield and reduced
cost of goods.
Results and Discussion
Depicted in Scheme 1 is the original synthesis of azaindole
16, including the preparation of 7-azaindole (3)26 from 2-ami-
nopicoline (1) and its transformation into the literature-known
4-nitro N-oxide 5.27 One major challenge was the formation of
the phenyl ether bond. We found that the 6-chloro atom in
compound 6 leads to increased reactivity of the building block
and can be easily removed later in the synthesis. Furthermore,
the N1-protection in 7 was crucial to avoid N-deprotonation
and subsequent rearrangement reactions.28 Despite considerable
improvements, the total yield over 15 steps was only 0.84%.
The depicted synthetic route was designed to allow for late-
stage variation of the 3-position by bromine substitution for SAR
investigations. However, with the 3-methyl group identified as
the most desirable substituent, its multistep introduction renders
the synthesis inefficient. A second major disadvantage of the
synthesis as depicted in Scheme 1 is the low yield of the
nitration step leading to compound 5. Reports in the literature
on the regioselectivity of the nitration of 7-azaindole N-oxide
(4) are contradictory.27 We observed the predominant formation
of the unwanted 3-nitro isomer and isolated a maximum 30%
yield of the 4-nitro analogue 5. As a second limitation, the
maximal scale of the reaction was 20-30 g for safety reasons.
The introduction of the methyl group on the azaindole moiety
early in the synthesis which would solve both these problems
failed. Several attempts to run a sequence starting with 3-methyl
7-azaindole were unsuccessful, and we were unable to get the
3-methylated pendant of intermediate 6.
In parallel, we developed the large-scale synthesis of
3-trifluoromethyl 7-azaindole (20) starting from 2-fluoropyridine
(17) (Scheme 2).29 In analogy to the former synthesis, ether 25
can be obtained from compound 20 in good yield. Notably,
the nitration step affording 22 works in 78% yield since the
trifluoromethyl group blocks the 3-position from competing
regioisomer formation.
We were intrigued by the notion of introducing the 3-methyl
group in 16 masked as a perfluorinated carbon. This would
require subsequent hydrodefluorination of the CF3 group in the
presence of a difluoroarene moiety.
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