Biomedical Engineering Reference
In-Depth Information
1.
1.
NMe
3
OH, CH
3
NO
2
, rt, 1 h
O
NMe
3
BH
4
O
(CF
3
CO)
2
O, CH
2
Cl
2
, rt, 1 min
NO
2
CH
2
Cl
2
, rt, 30 min (95%
)
2.
Cl
H
Cl
N
Cl
N
3.
NEt
2
, CH
2
Cl
2
, rt, 30 min
Cl
N
2.
NMe
3
RuO
4
9
10
11
CH
2
Cl
2
, rt, 24 h (95%)
87% (3 steps)
OTBDMS
1. 120°C, 48 h, sealed tube (100%)
2. TFA, CH
2
Cl
2
, rt, 1 min (90%)
12
OMs
OMs
O
NMe
3
BH
4
, CH
2
Cl
2
NMe
3
BH
4
, NiCl
2
.6H
2
O
1.
CH
2
Cl
2
, 0°C, 30 min
MeOH, rt, 3 h (89%)
95%
2.
DMAP
NH
2
NO
2
NO
2
Cl
N
Cl
N
Cl
N
MsCl, CH
2
Cl
2
, rt, 4 h (90%)
(±)-
15
(±)-
14
(±)
-
13
(PS-BEMP)
N
N
N
1.
t
-BuOK,
t
-BuOH,
μ
W, 30 x 1 min @ 100 W
P
1.
N
N
CH
3
CN, 4 h
2.
3.
SO
3
H, 30 min, rt
N
Cl
2.
NH
2
, CH
2
Cl
2
, 6 h
NH
3
, MeOH, rt, 30 min
N
71% (2 steps)
N
85% (3:1 mixture
exo
:
endo
)
(±)-
exo
-Epibatidine
17
Cl
(±)-
endo
-
16
SCHEME 11.2
Synthesis of the potent analgesic alkaloid (
)-epibatidine
17
.
product was purified by a catch-and-release process, catching onto an immobilized
sulfonic acid and then releasing by treatment with methanolic ammonia.
A necessary requirement of any new technology is to always compare it with
preexisting methods. To exemplify the potential of these new methods during a
contemporary drug synthesis, the erectile dysfunction drug sildenafil (Viagra
27
)
was chosen as a target (Scheme 11.3) [13].
The convergent strategy adopted for this synthesis of sildenafil
27
brought
together compounds
as the major coupling components that in turn were
easily derived from simple starting materials (
22
and
25
18
and
23
). The activated immobilized
ester
underwent amide bond formation, while the excess
amine was scavenged with an immobilized isocyanate resin in a separate step.
Cyclodehydration was achieved using sodium ethoxide under an early example of
focussed microwave conditions to afford multigram quantities of analytically pure
sildenafil in excellent overall yield.
A further example of these methods in contemporary drug synthesis was the
preparation of the bronchodilator (
R
)-salmeterol
25
and aminopyrazole
22
. Here, an alternative synthetic
pathway was used to avoid the problem of diastereomers encountered in previous
syntheses [20], allowing
34
to be prepared without any chromatographic purification
steps required (Scheme 11.4) [14]. Each transformation and product purification was
effected using immobilized reagents, although one recrystallization of
34
was needed
to enhance the diastereomeric purity of the product. The initial condensation of
phenol
30
28
with an immobilized methylene iminium salt to eventually form com-
pound
was also an important aspect of this synthesis. This involved a sequence of
reactions using an immobilized carbonate resin to effect deprotonation of
29
,
followed by reaction with Eschenmoser's salt to
ortho
-aminomethylate the phenol,
28
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