anticholinergic activity, and has been proposed for treatment of
Alzheimer’s disease. Condensation of piperidine aldehyde ( 10 ) with the
indanone ( 9 ) leads to the olefin ( 11 ). Catalytic reduction removes the
double bond to afforddonepezil( 12 ).^3
CH 3 O
CH 3 O
O
+
9
N
O=HC
CH 2 C 6 H 5
10
CH 3 O
CH 3 O
O
11 N CH 2 C 6 H 5
CH 3 O
CH 3 O
O
N CH 2 C 6 H 5
H 2
12
More recent work indicates that monoamine oxidase (MAO) inhibitors
may be useful as well. The indeneladostigil( 17 ) is intended to address
both of those targets; the compound thus incorporates a carbamate group
associated with anticholineric activity and a propargyl moiety found in
MAO inhibitors. The synthesis involves juggling protecting groups
on two reactive functions. Thus, reaction of amino-indanol ( 13 ) with
bis-tert-butoxy carbonate affords the corresponding t-BOC protected
derivative 14. Treatment of derivative 14 withN-methy-N-ethyl carbamoyl
chloride affords theO-acylated carbamate ( 15 ). Thet-BOC protecting
group is then removed by means of hydrogen chloride to give the free
amine ( 16 ). Reaction of 16 with propargyl bromide gives 17. This drug
also consists of a single (R) enantiomer; it is not clear from the source^4
at which stage the resolution takes place.
NH 2
HO
13
NHCO 2 BOC
14
tBuO 2 CO
HO N NHBOC
CH 3 CH 2
H 3 C O
O
15
HCl
NH 2
N
CH 3 CH 2
H 3 C O
O
16
Br
HN
N
CH 3 CH 2
H 3 C O
O
17
CH 3 CH 2 N
H 3 C
Cl
O
- INDENES 71