Chemistry Reference
In-Depth Information
15.2 Carbon-Carbon Bond Formation
15.2.1 Suzuki-Miyaura Coupling
The Suzuki-Miyaura reaction is the transition metal-catalyzed coupling of an
organoboron nucleophile with an electrophilic partner such as an organo-
halide or activated alcohol (e.g., sulfonate). Initially reported in 1979,
52
the
Suzuki reaction has become the most prevalent tool for the formation of
aryl-aryl bonds. The process group at Merck published one of the earliest
pharmaceutical examples of Suzuki coupling for the synthesis of losartan in
1994.
10
Since that time, this named reaction has been the most frequently
reported Pd-catalyzed transformation for the large-scale synthesis of drug
candidates.
53
The popularity of this coupling for the synthesis of highly
functionalized compounds stems from its broad functional group com-
patibility and the commercial availability of many boronic acids and esters.
Like most transition metal-catalyzed couplings, the Suzuki reaction can be
sensitive to oxygen, but thorough inertion can minimize issues from oxygen
contamination. Nickel can be an alternative catalyst to Pd for this transfor-
mation, although this is much less common.
54
Environmental consider-
ations are paramount when scaling any process and the green aspects of the
Suzuki reaction have been reviewed previously.
55
The recent applications of
the Suzuki reaction in total synthesis have also been reviewed.
56
The process group at Amgen implemented the Suzuki coupling of bromide
1 and boronic acid 2 for the synthesis of p38 MAP kinase inhibitor 4 for the
treatment of conditions such as rheumatoid arthritis, Crohn's disease and
psoriasis (Scheme 15.1).
53ar
A screen of various parameters including cata-
lyst, base and solvent revealed PdCl
2
(A-Phos)
2
,K
3
PO
4
and IPA/H
2
O as the
optimal conditions for this cross-coupling. In particular, the process team
was interested in avoiding class 2 solvents (hence IPA and H
2
O) and noted
K
3
PO
4
as a privileged base for large-scale Suzuki couplings that performs
well for a wide range of substrates and does not off-gas upon neutralization.
i. separate phases
ii. crystallization from aqueous
with IPA and 2 M aq HCl
70 to 20 ºC
Br
(HO)
2
B
CO
2
H
CO
2
K
N
N
2
(1.05 equiv)
N
N
Me
O
N
F
N
Me
O
F
PdCl
2
(A-Phos)
2
(0.1 mol%)
K
3
PO
4
(3.0 equiv)
H
2
O/IPA (2:1), 85 ºC, 1 h
93%
F
F
1
3•K
H
N
CO
2
H
Me
2
N
N
N
CDI
c
-PrNH
2
O
N
N
N
Me
O
N
Me
O
F
F
P(
t
-Bu)
2
A-Phos
F
F
3
(2.05 kg)
<0.5 ppm Pd
4
Scheme 15.1
Suzuki coupling for the synthesis of p38 MAP kinase inhibitor 4.
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