Organic Chemistry of Drug Synthesis. Volume 7

The hormone melatonin ( 30 ) is intimately involved in the diurnal cycle
with levels rising late in the day prior to sleep. Congeners have as a result
been prepared in the search for a sleep inducing drugs.Ramelteon( 29 ), an
indene that incorporates several structural features of the hormone, has
been approved by the FDA as a sleeping aid. The first part of the synthesis
involves construction of the ethylamine side chain. Thus condensation of
indanone ( 18 ) with the yilde from 2-diethoxyphoshonoacetonitrile attaches
the requisite two carbon chain ( 19 ). The nitrile is then reduced to the cor-
responding primary amine ( 20 ) by means of Raney nickel. This drug also
follows the current trend toward a chiraly defined substance. Reduction
of the double bond with rhodium in the presence of the chiral catalyst
2,2^0 -bis(diphenylphosphino)-1,1^0 -binaphthyl (BiNAP) affords the intermedi-
ate ( 21 )asthe(S) enantiomer. This compound is then acylated with propionyl
chloride to afford 22. The remainder of the scheme involves construction
of the fused furan ring. Bromination proceeds at the slightly less hindered
position. The methoxy group is then cleaved with boron tribromide to
yield the bromophenol ( 23 ). Alkylation of the phenol with allyl

CH O

3 O

18

(C 2 H 5 O) 2 POCH 2 CN

CH 3 O

19

CN

NiCH^3 O

20

NH 2

CH 3 O

21

NH 2

Rh

BiNAP

C 2 H 5 COCl

CH 3 O

NHCOC 2 H 5

22

HO

NHCOC 2 H 5

23

Br

1. Br 2
   Br 2. BBr 3

NHCOC 2 H 5

Br

O

24

200°C

NHCOC 2 H 5

Br

HO

25

NHCOC 2 H 5

Br

HO

O=HC

O 3 NaBH^4

NHCOC 2 H 5

Br

HO

HO

(^2627)
NHCOC 2 H 5
HO
HO
28
H 2 /Pd

1. CH 3 SO 2 Cl
   2. TEA

NHCOC 2 H 5

29

O

NH

NHCOCH 3

30

CH 3 O

72 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING