Chemistry Reference
In-Depth Information
n-Bu
3
SnNEt
2
,
151
numerous improvements have been implemented to
streamline this type of reaction, especially through the work of Buchwald's
and Hartwig's groups.
152
The harsh reaction conditions of the original
Ullmann coupling that employed stoichiometric copper and high tempera-
tures
153
have now been replaced by milder, catalytic methods that can be
applied to more complex substrates. These advances in aromatic amine
preparation have found widespread use in the areas of natural product
synthesis
154
and for the preparation of other materials of interest.
155
In
process chemistry, the Buchwald-Hartwig cross-coupling has gained in-
creasing importance in the synthesis of pharmaceutical candidates due to
the preeminence of aromatic amines in current drug substances.
156
Aryl
bromides and iodides have commonly been used, but more inexpensive and
readily available aryl chlorides can also serve as substrates. Recent advances
in Pd-catalyzed amination facilitated by sterically demanding ligands have
been reviewed.
157
Researchers at Eli Lilly described the preparation of JAK2 inhibitor
LY2784544 (151), a drug candidate for the treatment of several myeloproli-
ferative disorders (Scheme 15.34).
156i
During the first-generation synthesis of
151, conditions developed for the coupling of 148 and an analog of 149 were
also applied to the coupling of 148 and 149 without extensive optimization.
Since the coupling with 149 was slower than with the N-PMB analog (most
likely due to steric reasons), xylenes were chosen over toluene to run the
reaction at higher temperature (xylene-water azeotrope at 99-103 1C). In the
plant, to a mixture of 148, 149 and aqueous NaOH in xylenes was added
Xantphos (0.8 mol%) and Pd
2
(dba)
3
(0.4 mol%). The resulting mixture was
then heated at reflux for 40 h, followed by cooling to below 60 1C, dilution
with THF (to solubilize 150), filtration through Celite to remove insoluble
material, phase separation and an aqueous wash. The resulting organic
phase was treated with SiliaBond Thiol from SiliCycle (Pd scavenger, 8.2 wt%
per 148) at 50-60 1C for 10 h. Filtration, concentration of the filtrates and
addition of heptane crystallized 82.4 kg of 150 in 79% yield. It was men-
tioned that during scale-up runs, the slower kinetics of the reaction allowed
the formation of larger quantities of a by-product that was characterized as
the bis-addition product of 149 to both chloride groups on the molecule.
i.
Pd
2
(dba)
3
(0.4 mol%)
XantPhos (0.8 mol%)
NaOH, xylenes/H
2
O(6:1)
reflux, 40 h
filtration
aqueous workup
SiliaBond thiol silica
(8.2 wt% per
148
), xylenes/THF
50
O
O
N
N
ii.
iii.
iv.
N
N
TFA
151
(LY2784544)
(R = H)
+
N
N
NH
2
N
R
H
Cl
N
N
N
H
2
O
t
-Bu
60 ºC, 10 h
filtration and concentration
crystallization from
heptane/xylenes
−
150
(R =
t
-Bu)
(82.4 kg)
F
F
v.
vi.
Cl
Cl
148
149
(1.05 equiv)
79%
Scheme 15.34 Pd-catalyzed amination en route to LY2784544.
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