Organic Chemistry of Drug Synthesis. Volume 7

that ring due the presence of both the ether and the amine functions.
Construction of the second ring begins with the alkylation of the phenolic
hydroxyl in 50 with ethyl bromoacetate to yield the ether ( 51 ). The
benzylic hydroxyl is then replaced by chlorine by means of thionyl chlor-
ide. Condensation of the anion from the indole with the benzylic chloride
( 52 ) introduces the remaining benzene ring ( 53 ). The ester on the pendant
side chain is next reduced to the corresponding alcohol using lithium
aluminum hydride. The terminal hydroxyl is then replaced by bromine
in a reaction with carbon tetrabromide in the presence of triphenylpho-
sphine to afford intermediate 54. Alkylation of 54 with azepine completes
construction of the side chain. Catalytic hydrogenation removes the benzyl
protecting groups, uncovering the phenolic hydroxyl groups. This affords
the estrogen antagonist bazedoxifene ( 55 ).^8
The “triptan” class of 5-HT 3 serotonin antagonists have found extensive
use as drugs for treating migraine headaches. The synthesis of one recent
example starts with reaction of the benzylsulfonyl chloride ( 56 ) with pyr-
rolidine to afford the sulfonamide ( 57 ). Hydrogenation of this intermediate
reduces the nitro group to the corresponding aniline ( 58 ). This function is
then transformed to a hydrazine by the conventional scheme involving
conversion to the diazonium salt by reaction with nitrous acid followed
by reduction of this last compound with stannous chloride. Condensation
of this product ( 59 ) with 4-chlorobutyraldehyde gives the hydrazone.
Fischer indolization of this last derivative by means of acid affords the
indole ( 60 ). Chlorine on the side chain is then replaced by a primary
amine ( 61 ). Reaction of 61 with formaldehyde and sodium borohydride
converts the amine to itsN,N-dimethyl derivative. Thus, the 5-HT 3 anta-
gonistalmotriptan( 62 ) is obtained.^9

ClO 2 S

NO 2

56

NH SO 2

NR 2

N

57 ; R = O

58 ; R = H

1. NaNO 2 , H+
   2. SnCl 2

SO 2

NH

N

NH 2

59

O=HC Cl

H+

NSO

60

NH

Cl

SO 2 NH 3

N

61

NH

NH 2

NaBH 4

NSO 2

62

NH

N(CH 3 ) 2

CH 2 =O

The same general approach is used for the somewhat more complex
“triptan” avitriptan ( 71 ). Synthesis of the substituted pyrimidine for

146 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING