Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 724

only 0.75 mol% in NMP as solvent without adverse effects. In the laboratory,
to a degassed solution of 53 (50 g) and 54 at 45 1C (to help dissolve the two
reactants and prevent foaming during nitrogen-vacuum purge cycles) was
added Pd(OAc) 2 (1 mol%) followed by further degassing and heating to
100 1C. Upon completion of reaction (2 h; formation of a black precipitate,
presumably Pd black, coincided with the end of the reaction), the dark
mixture was cooled to room temperature and treated with BHT to prevent air
oxidation. This NMP solution of intermediate 55 was telescoped directly into
the next step (olefin hydrogenation). It was mentioned that the Pd from the
Heck coupling was sucient to catalyze the subsequent olefin reduction but,
in order to ensure full conversion (Z99.8%) to the saturated intermediate,
5 wt% of 10% Pd/C was added. No information was provided about the level
of residual Pd after the Heck or hydrogenation steps or in the final API.
The preparation of drug candidate 61, a neuropeptide calcitonin gene-
related peptide receptor inhibitor for the treatment of migraine, was
described by the process group at Bristol-Myers Squibb (Scheme 15.12). 80x A
Heck coupling was implemented between iodoaniline 58 and aminoacrylate
59 in the presence of only 0.005 mol% Pd(OAc) 2 , TBAC (0.5 equiv.; catalyst
stabilizer) and K 2 CO 3 in a 1:1 THF-H 2 O mixture at 65-70 1C with no add-
itional ligand. Upon completion of reaction (5 h), the mixture was diluted
with THF-H 2 O and filtered through Celite and a 10 mm Cuno cartridge in-
line filter to remove Pd by-products. After an aqueous work-up, the organic
phase was concentrated and, following a solvent swap to MeOH, water was
added to crystallize Heck product 60 in 66% yield and 94.1% purity. Inter-
mediate 60 was then subjected to an extensive purification protocol that
consisted of conversion to its mesylate salt followed by freebasing with
aqueous, methanolic K 2 CO 3 and an additional recrystallization from EtOAc
to afford 14.7 kg of 60 (45% overall yield) with 98% purity. No information
was provided on the level of residual Pd in 60.

NH 2

i. Pd(OAc) 2 (0.005 mol%)
TBAC (0.5 equiv)
K 2 CO 3 ,THF/H 2 O(1:1)
65-70 ºC, 5 h

NH 2 ￿HCl

+

MeO 2 C NHCO 2 Bn

NHCO 2 Bn

ii. filtration to remove insoluble
Pd residue
iii. aqueous workup
iv. crystallization from H 2 O/MeOH

59
(1.25 equiv)

I

CO 2 Me

58

60
(25.2 kg)
94% purity

66%

i. dissolution in
hot EtOAc
ii. filtration through
Celite
iii. crystallization
from EtOAc
86%

N

i. MsOH (1.1 equiv)
CH 2 Cl 2 /IPA (11:1)
5ºCto20ºC,3.5h

N

60
(14.7 kg)
98% purity

60
(18.3 kg)
97.6% purity

ii . K 2 CO 3 (1.25 equiv)
H 2 O/MeOH (1:1.3)
80%

O

N H
O

NH

Me N N N N

O

61

Scheme 15.12 Heck coupling for the preparation of aminoacrylate 60.