Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 728

afforded 74 but the naphthyl ester was chosen since it is a crystalline solid
that facilitated the isolation of 72. No information was provided on the levels
of residual Pd in 74.

15.2.9 Carbonylation
The first report on the Pd-catalyzed carbonylation of aryl and vinyl halides
was disclosed by Heck's group 40 years ago. 106 Since then, the transition
metal-catalyzed carbonylation reaction has been used extensively in both
academia and industry for the synthesis of natural products and pharma-
ceuticals. Aryl halides, sulfonates and diazonium salts can be used as sub-
strates. Depending on the reaction conditions, aldehydes, ketones and
carboxylic acid derivatives can be readily accessed under very mild con-
ditions that are compatible with many other functional groups. Some of the
drawbacks of this reaction are the need for specialized equipment and the
toxicity of CO. As an alternative to carbonylations run in batch mode, flow
reactors represent an attractive approach particularly well suited for large-
scale manufacturing. 107 Transition metal-catalyzed carbonylations have
been reviewed. 108 Many examples of large-scale Pd-catalyzed carbonylations
have been reported starting in the late 1990s, which show the interest in this
technology by process chemistry groups. 109
Wei and co-workers at Boehringer Ingelheim in the United States have
reported the synthesis of sodium-hydrogen exchange type 1 inhibitor 78,a
drug candidate for the treatment of several heart diseases (Scheme 15.16). 109j
The introduction of the ester functionality was accomplished via a Pd-cata-
lyzed carbonylation reaction on aryl bromide 76. A ligand screen (dppp, dppf
and BINAP) using Pd(OAc) 2 as metal source with K 2 CO 3 as base in MeOH at
70 1C and 100 psi of CO showed the highest conversion with dppp. Add-
itional experimentation with the Pd(OAc) 2 /dppp catalytic system revealed
that at higher temperature (110 1C), a faster reaction rate was observed but at
the expense of generating up to 27% of carboxylic acid 79 (Figure 15.4).
However, the use of Et 3 N at a slightly lower temperature (90 1C) minimized

CO (100 psi)
Pd(OAc) 2 (0.2 mol%)
dppp (0.22 mol%)
Et 3 N, MeOH
90-92 ºC, 20 h

F 3 C Br

F 3 C CO 2 Me

AcN

AcN

76 77

MeOH solution

i. MeOH distillation
ii. N -acetyl- L -cysteine (3 mol%)
NMP, 60 ºC, 30 min
iii. H 2 O to crystallize
iv. seeding with 77
v. cooling to 20-22 ºC

O NH

NH 2

F 3 C

77
(2.12 kg)
4.1 ppm Pd

H

AcN

78

94%

Scheme 15.16 Carbonylation reaction for the synthesis of methyl ester 77.