Organic Chemistry of Drug Synthesis. Volume 7

the nitrobenzoyl chloride 38 proceeds in straightforward fashion to the
amide ( 39 ). Reduction of the nitro group by means of hydrogenation or
stannous chloride affords the corresponding aniline ( 40 ). Acylation of the
newly formed amino group with the benzoyl chloride ( 41 ) then affords
lixivaptan( 42 ). An alternate approach assembles the full side chain and
then attaches that to the heterocycle 37.^5
Antiandrogens have proven very useful in treating BPH, an all too fre-
quent accompaniment of aging. These agents, in addition, have a minor
place in the treatment of prostatic cancer. They are also, on a more
trivial note, used to reverse hair loss due to male pattern baldness. Drugs
that act as antiandrogens, such finasteride and dutasteride (Chapter 2),
generally act by inhibiting the enzyme 5-a-reductase, which converts pre-
cursors, such as testosterone, to their active form by reducing the double
bond at the 4-position in the steroid A ring. These drugs, formally
derived from steroids, all retain the bulk of the precursor nucleus. A pair
of more recent, closely related, compounds retain the lactam A ring of
the steroid-derived agents, but replace steroid rings C and D by a simple
aromatic ring. These agents retain the 5-a-reductase activity and have as
a result been tested in the clinic as potential agents for treating cancer of
the prostate. The first step in the synthesis ofbexlosteride( 49 ) comprises
conversion of the tetralone ( 43 ) to its enamine by reaction with pyrrolidine.
Reaction of 44 with a large excess of acrylamide under carefully controlled
conditions leads to formation of the unsaturated lactam ( 45 ). The sequence
can be rationalized by assuming that the first step comprises conjugate
addition to the acrylamide; displacement of the pyrrolidine by amide nitro-
gen completes ring formation. The double bond at the ring fusion is next
reduced with triethylsilane in the presence of trifluoroacetic acid. Thus,
the saturated lactam that consists largely of racemic isomer with the trans

Cl

O

Cl

N

CONH 2

Cl

O NH

Cl

O N

(^43444546)
HCl
Cl
CH 3 O 2 CHN
CH 3
47
Cl
CH 3 O 2 CHN
CH 3
48
CH 3

1. Et 3 SiH


2. CH 3 Cl

Cl

O N

49

CHR

H

H

Separate

Resolve

CH 3 OH

Na 2 CO 3

222 POLYCYCLIC FUSED HETEROCYCLES