Organic Chemistry of Drug Synthesis. Volume 7

N
O NaH

H 5 C 2 O 2 CCl

1

N C 6 H 4 Cl

O

H 5 C 2 O 2 C

2

1. H 2 S


2. H 2

NH

S

O

3

NH

S

CH 3 CO

4

F

Br

+ NC

6

Mg

F

O

N

S

CH 3 CO O

F F

O

Br

NBS

5

(^789)
C 6 H 4 Cl
g-Aminobutyric acid is the main inhibitory brain neurotransmitter and is thus
involved in many psychological process. Muscimol ( 10 ), the GABA agonist
from theamanitamushroom, for example, produces inebriation. A close ana-
logue,gaboxadrol( 15 ) in which the pendant side-chain amine is closed to
form a piperidine is currently being investigated as a sleep aid. The drug
reduces insomnia and improves the quality of sleep. The synthesis of this
compound begins by forming the acetal from 11 by reaction of the com-
pound with ethylene glycol. ( 12 ). Reaction of this intermediate with hydro-
xylamine replaced the ethoxy group in the ester to addord the hydroxamic
acid ( 13 ). Treatment of that intermediate with acid leads first to hydrolysis
of the ketal; reaction of the terminal hydroxyl on the hydroxylamine group
with the ketone leads to closure to the isoxazole ring. Hydrolysis under
more strenuous conditions frees the piperidine nitrogen to afford 15.^3
O
NH
H 2 N
10
CH N
3 O 2 C O
CO 2 C 2 H 5
11
OH
OH
CH N
3 O 2 C O
O
12
NH 2 OH
CH N
3 O 2 C O
O
13
NH 2 OH
O
OC 2 H 5
O
HCl
CH N
3 O 2 C
14
O
NH
O
HBr
HN
15
O
NH
O
Muscimol
O
The ACE inhibitors, first introduced almost three decades ago, expanded
the means of treating hypertension by providing yet another mechanism for
lowering blood pressure. The pioneer drug, captopril, was followed on the
market by well over a dozen other ACE inhibitors. Current research
focuses on compounds that will inhibit vasopeptidases, a category of
190 BICYCLIC FUSED HETEROCYCLES