Organic Chemistry of Drug Synthesis. Volume 7

group is then removed under reductive conditions. This last reaction affords
efavirenz( 121 ) as a single enantiomer.^19

Cl

NH 2

112

ClOC(CH 3 ) 3 Cl

NHCOC(CH 3 ) 3

113

1. BuLi

114

Cl

NHCOC(CH 3 ) 3

O

CF 3

HCl

115

Cl

NH 2

O

CF 3

116

Cl O

CF 3

117

Li

C 6 H (^5) N
OH
118
OCH 3
Cl
NH
OH
F 3 C
COCl 2
OCH 3
NH
OCH 3
Cl
OCH 3
Cl
N
F 3 C
O
O
120 119
Ce(NO 3 ) 2
NH 4 NO 3
Cl
NH
F 3 C
O
O

2. CF 3 CO 2 C 2 H 5

121

The structural promiscuity of the estrogen receptors has led to the devel-
opment of a host of nonsteroidal agonists and antagonist. Nonsteroidal
compounds that bind to either progestin or androgen receptors have, on
the other hand, proven far more elusive, arguably because of the more
rigid structural demands at those sites. A benzoxazine has very recently
been found to act as a potent agonist at progesterone receptors both
in vitroandin vivo. Molecular modeling suggests that the benzoxazine
moiety in this compound fulfills the role of the steroid AB rings while
the pyrrole fulfills the role of the D ring in progesterone.^20 Construction
of the benzoxazine starts with the Grignard reaction of anthranilate 122
with methylmagnesium bromide. Treatment of the product ( 123 ) with
carbonyl diimidazole closes the oxazole ring 124. In a convergent
scheme, reaction ofN-protected imidazole 125 with butyllithium followed
by trimethyl borate affords the boric acid derivative 126. Condensation of
this acid with benzoxazole 124 in the presence of the palladium/triphenyl-
phosphine catalyst affords the coupling product 127. Treatment of 127 with
isocyanosulfonyl chloride adds the required cyano function to the pyrrole
128. The protecting group on the imidazole is then removed by means of
sodium ethoxide. The free amine is next methylated by means of methyl

2. COMPOUNDS WITH TWO HETEROATOMS 177