Chemistry Reference
In-Depth Information
SO
2
Me
MeO
2
S
SO
2
Me
20
21
Figure 15.2 By-products from Negishi coupling en route to 19.
n
-BuMgCl (2 M in THF,
1equivvs.
22
),
−
i.
NC
60 min
ZnCl
2
(0.5 M in THF,
0.5 equiv) vs.
22
−
18 ºC, 30
−
Ph
OMe
ii.
OMe
i. Na
2
CO
3
(aq.)
CH
2
Cl
2
I
60 min;
then to 25 ºC over 2 h
18 ºC, 30
−
O
N
N
N
N
H
OMe
N
H
ii. crystallization
from MeOH
N
O
iii.
OMe
N
N
22
(3 equiv)
N
N
N
60%
H
23
(1 equiv)
24
(158 g)
N
N
H
24
HCl
N
25
(BMS-599793)
Cl
N
PdCl
2
(dppf)CH
2
Cl
2
(10 mol%)
58 ºC, 8 h
iv.
v.
aqueous workup
1.5 M HCl
Scheme 15.4
Synthesis of 24 via Negishi coupling en route to BMS-599793.
and Zn, respectively. The two main by-products from the Negishi coupling
were 20 from homocoupling and deschloro-21 (Figure 15.2). Excess Zn (3
equiv.) minimized the formation of 20 and both were removed in the filtrates
after the crystallization of Negishi product 18.
A collaboration between Princeton API Services, J-Star Research, Scino-
Pharm Taiwan and the International Partnership for Microbicides (IPM)
resulted in the publication of the large-scale synthesis of BMS-599793 (25), a
small-molecule HIV entry inhibitor developed by Bristol-Myers Squibb which
was licensed to IPM to develop a topical microbicide for use in poor coun-
tries (Scheme 15.4).
58k
Medicinal chemistry employed a Stille coupling be-
tween 2-(tributylstannyl)pyrazine and a 7-chloro-6-azaindole to assemble the
biaryl moiety of the molecule as the last step of the synthesis. However, the
organotin reagents were expensive, toxic and diculty to purge, which made
this approach impractical. As alternatives, Suzuki and Negishi couplings
were investigated and, based on impurity profiles and reaction kinetics, the
researchers opted for developing the Negishi approach. Thus, 2-iodo-
pyrazine (22) was treated with n-BuMgCl at
18 1C to generate the corres-
ponding Grignard reagent. Low temperature was required to prevent the
alkylation of the pyrazine via reaction of the Grignard formed with n-butyl
halide by-product. Also, 1 equiv. of n-BuMgCl was employed, since excess
Grignard reagent competed with the piperazine in the subsequent coupling
with azaindole 23. After pyrazine-Grignard formation, the addition of a THF
solution of ZnCl
2
followed by warming to 25 1C produced the desired
organozinc reagent. The stoichiometry of the ZnCl
2
was also important: 1
equiv. per 22 provided an organozinc that performed well in the Negishi
coupling, but better results were obtained when only 0.5 equiv. was
Search WWH ::
Custom Search