Organic Chemistry of Drug Synthesis. Volume 7

( 107 ) was interestingly first described in a 1979 patent.^12 Data on this agent
using more recent pharmacological methods apparently led to its being
pulled off the shelf. Condensation of the acid chloride ( 102 ) with
N-methylglycine ethyl ester leads to the amide ( 103 ). Treatment of 103
with potassiumtert-butoxide leads the enolate adjacent to the aromatic
ring to add to the ester at the end of the side chain, thus forming the pyr-
rolidine ring ( 104 ¼ 105 ). Heating this intermediate ( 105 ) in PPA leads to
reaction of the ketone carbonyl group with the other aromatic ring to form
the benzoxazine ( 106 ). The unsaturation in the seven-membered ring is
then reduced by means of sodium in liquid ammonia leading to the
product with a trans ring junction. The amide function is then taken on
the amine by means of a metal hydride. Resolution, not described in the
patent, will then afford chiral 107.

O

Cl

102

Cl

O

O

Cl

N

O

O

OC 2 H 5

O

O Cl

N O

O

O Cl

N O

PPA

103

104

105

O

Cl

N O

NH CO 2 C 2 H 5

[H]

O

Cl

N

H H

107 106

tBuOK

The structures of the vast majority of PD-5 inhibitor compounds aimed
at erectile dysfunction consist of modified purines. The structure of the
recently approved drug for this indicationtadalafil( 113 ) differs markedly
from the prototypes. Tryptophan methyl ester ( 108 ) provides the starting
material for large scale enantioselective synthesis. Condensation of that
compound with piperonal ( 109 ) in the presence of acid leads to formation
of the tricyclic intermediate ( 110 ). This transform involves initial addition
of the amine to the aldehyde. The carbocation from the newly formed
carbinolamine then attacks the indole 2-position to form the the fused
piperidine. The stereochemistry of the new chiral center is guided by
that from the tryptophan carbon across the ring. The secondary amine is
next acylated with chloroacetyl chloride in the presence of triethylamine
to afford 111. Reaction of this intermediate with methylamine goes on to
form the desired product in a single step. This reaction can be rationalized

2. COMPOUNDS WITH FOUR FUSED RINGS 229