Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 722

MeO

H
N

Pd(OAc) 2 (0.5 mol%)
DABCO (2 equiv)
MeOH, 65 ºC, 3 h

O I SO 2 Et

OH

+

N

BocHN

CF 3

F

49
(1.01 equiv) 48

SO 2 Et

MeO SO 2 Et

H
N

i. DBU (1.5 equiv)
50 ºC, 2 h

N O

N

OH

OH

ii. Crystallization f rom
MeCN/H 2 O, 25 ºC

N
H

NHBoc CF 3

CF 3

F

82%

50
(not isolated)

51
(36.7 kg)
8.2 ppm Pd

SO 2 Et

H 2 N O

N

OH

52
(BI 653048 BS)

N
H

CF 3

￿K 3 PO 4

F

Scheme 15.10 Synthesis of intermediate 51 via Sonogashira coupling and cycliza-

tion en route to BI 653048 BS.

cyclization. On a large scale, the researchers investigated a one-pot
Sonogashira-cyclization sequence to couple alkyne 48 with aryl iodide 49
and thus avoid the isolation of intermediate 50. Reaction optimization for
the Sonogashira step showed that Pd(OAc) 2 gave the best results compared
with other Pd sources and that, by performing the coupling in the absence of
Cu salts, complete conversion and minimization of alkyne homocoupling
were obtained. After screening bases (NaOMe, N-methylpyrrolidine, Et 3 N,
DBU, quinuclidine, i-PrNEt, piperidine, tetramethylguanidine, DABCO) and
solvents (MeOH, EtOH, n-PrOH, IPA), DABCO and MeOH were selected for
scale-up work. Unfortunately, no Sonogashira coupling was observed with
DBU, which would have eliminated the need for two bases. In the plant, a
mixture of 48, 49 (1.01 equiv.), Pd(OAc) 2 (0.5 mol%) and DABCO (2 equiv.) in
MeOH was heated at 65 1C for 3 h. Upon completion of coupling, DBU (1.5
equiv.) and further stirring at 50-55 1C effected the cyclization of 50 with loss
of the Boc group to afford 51. The isolation of 51 involved the addition of
MeCN followed by water at 45-55 1C, seeding with crystals of 51 (0.005 wt%
per 48) and cooling to 25 1C to produce 36.7 kg of 51 in 82% yield with only
8.2 ppm Pd. These crystallization conditions afforded a fast-filtering solid in
contrast to the original protocol using MTBE-water to precipitate 51, which
gave a very slow filtration rate and also higher residual Pd (30-70 ppm).

15.2.6 Heck Coupling
The Heck reaction has become an indispensable technology for C-C bond
formation and it is currently second only to the Suzuki cross-coupling in
number of applications. 2 In agreement with this statement, numerous
inter- 80 and intramolecular 81 examples can be found in the field of process