Chemistry Reference
In-Depth Information
A possible explanation for the slower rate of cross-coupling is that poorer
mixing of the biphasic mixture resulted in a base-starved organic phase.
However, recrystallization from H
2
O-IPA was able to reduce the level of this
impurity to
o
0.5% (even though this protocol was not implemented in the
plant based on the experimental section of the article). No information was
provided on the level of residual Pd in 150 after the functionalized silica
treatment.
Goodyear and co-workers at Merck reported the large-scale synthesis of
non-nucleoside reverse transcriptase inhibitor MK-6186 (155), a drug can-
didate for the treatment of HIV infection (Scheme 15.35).
156l
The formation
of intermediate 154 was accomplished through the Pd-catalyzed coupling of
aryl bromide 152 and benzophenone hydrazone (153), which is a convenient
and easier to handle substitute for hydrazine hydrate on a large scale
(NH
2
NH
2
H
2
O had been employed by the medicinal chemistry group in the
original synthesis of 154). The use of strong bases promoted the formation of
amidine 156, whereas weaker bases (K
3
PO
4
,Cs
2
CO
3
) in combination with
very active ligands such as Xantphos, DPEPhos and BINAP afforded by-
product 157 in addition to 154. A ligand screen revealed that the best
combination to minimize impurity formation was Pd
2
(dba)
3
/dppf together
with saturated, aqueous K
3
PO
4
in CPME. Further optimization led to the use
of PdCl
2
(dppf)
CH
2
Cl
2
,2MK
3
PO
4
and toluene as solvent, which afforded
complete conversion after 19 h at reflux. In the plant, to a degassed solution
of 152 and 153 in toluene was added the Pd precatalyst (2 mol%) followed by
further degassing. A degassed aqueous 2 M K
3
PO
4
solution was then added
and the resulting mixture was refluxed for 19 h. After cooling and an
aqueous work-up, the toluene layer was treated with macroporous poly-
styrene-2,4,6-trimercaptotriazine (MP-TMT; polymer-bound 2,4,6-tri-
mercaptotriazine) at 20 1C for 17 h to remove residual Pd and Fe. Following
CN
PdCl
2
(dppf)CH
2
Cl
2
(2 mol%)
K
3
PO
4
,PhMe/H
2
O(1:1)
reflux, 19 h
aqueous workup
i.
CN
Cl
O
OMe
NH
2
ii.
iii.
iv.
v.
N
+
Cl
Cl
O
OMe
OMe
MP-TMT resin (72 wt% per
152
)
PhMe, 20 ºC, 17 h
filtration and concentration
crystallization from IPA/PhMe
Cl
Ph
Ph
OMe
NH
N
Ph
Br
153
(1.05 equiv)
152
154
(7.0 kg)
Ph
79%
Ph
CN
N
NH
2
CN
Ph
N
HN
O
OMe
Cl
O
Cl
O
OMe
Ph
N
Ph
Cl
Cl
OMe
Cl
OMe
N
N
NH
N
NH
N
Ph
NH
N
Ph
155
(MK-6186)
N
Ph
156
157
Ph
Scheme 15.35 Buchwald-Hartwig amination with benzophenone hydrazone.
Search WWH ::
Custom Search