Organic Chemistry of Drug Synthesis. Volume 7

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

1. INDENES 71