Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 750

Cl NH 2

i. Pd 2 (dba) 3 (1 mol%)

cyclohexyl JohnPhos (3 mol%)
PhMe, 63 ºC, overnight
aqueous workup
filtration through Celite
1 N HCl/MTBE
10 N NaOH (to pH = 11.5)/MTBE
crystallization from heptane/cyclohexane
86%

N N

Me 3 Si SiMe 3

+

N

ii.
iii.
iv.
v.
vi.

O

O Li

N

N

159
1MinTHF
(1.1 equi v)

158 160

(443 g)

Scheme 15.36 Buchwald-Hartwig amination using LHMDS as an ammonia
surrogate.

filtration and concentration, the addition of IPA and cooling to 0 1C crys-
tallized 7.0 kg of 154 in 79% yield. No information was provided on the level
of residual Pd in 154 or final API.
The process group at Hoffmann-La Roche reported the preparation of
aniline 160, a key component in several Bruton's tyrosine kinase (BTK) in-
hibitors under development for the treatment of rheumatoid arthritis
(Scheme 15.36). 156o The conversion of 2-chloropyridine 158 into amine 160
required the use of ammonia or an appropriate surrogate, such as
LHMDS, 158 or tert-butyl carbamate. 159 Since the latter approach failed, the
researchers opted for optimizing the introduction of the amino group via
LHMDS (159). Initial experimentation showed that Pd 2 (dba) 3 and 2-(dicy-
clohexylphosphino)biphenyl (cyclohexyl JohnPhos) in THF worked well
on a small scale but, on scale-up, multiple Pd and ligand charges were
necessary to achieve complete conversion. The use of 2-(di-tert-butyl-
phosphino)biphenyl (JohnPhos) slowed the cross-coupling reaction whereas
NaHMDS provided only trace amounts of amine 160. More reproducible
results on scale were obtained when THF was replaced with toluene and
when a THF solution of LHMDS was slowly added to a mixture of 158 and
Pd 2 (dba) 3 /ligand. On a large scale, a degassed solution of 158,Pd 2 (dba) 3
(1 mol%) and cyclohexyl JohnPhos (3 mol%) in toluene at 45 1C was treated
with a 1 M solution of LHMDS in THF (one-quarter of the total volume of
solution) over 5 min. Following an exotherm that increased the internal
temperature to 48 1C, the mixture was heated to 62 1C and the remainder of
the LHMDS solution was added over 90 min. The reaction mixture was then
stirred at 63 1C overnight. After an aqueous quench and phase separation,
the toluene layer was filtered through Celite to remove Pd by-products and
concentrated. The residue was redissolved in MTBE and extracted with 1 N
HCl to form the water-soluble HCl salt while leaving the non-basic impur-
ities in the organic layer. After neutralization with 10 N NaOH to regenerate
the free base of 160 (pH adjustment to 11.5) and extraction into MTBE, a
solvent switch to 2-MeTHF followed by a second solvent switch to cyclo-
hexane and addition of heptane crystallized 443 g of 160 in 86% yield. The
level of residual Pd in 160 was not disclosed, but it was mentioned that
several subsequent steps also employed Pd catalysts, which made its removal
at this stage unnecessary.