(The reagents used for these last two steps almost guarantee that this is not
the route used for larger scale synthesis.) Catalytic hydrogenation then
reduces the resulting azide to the corresponding aniline. Saponification
of the ester leads to amino acid 103. The amine is then diazotized and
the diazonium salt treated with hydrogen bromide to afford bromo deriva-
tive 104. Condensation of this last intermediate with the magnesium salt
from ethyl malonate leads in a single step to the requisiteb-ketoester
( 105 ). The extra carbon required to build the fused ring is added in this
case by reaction with DMF acetal ( 106 ). The methyl enol ether is then dis-
placed as above by cyclopropylamine ( 107 ). Treatment of the product with
base closes the ring to afford the quinolone ( 108 ). Suzuki cross-coupling of
the bromine atom in 108 with the boronic acid from dihydroisoindole 109
leads to the coupling product ( 110 ). The trityl protecting group on isoin-
dole nitrogen is then removed by treatment with acid. Thus the quinolone
garfenoxacin( 111 ) is obtained.^18
2. COMPOUNDS WITH TWO HETEROATOMS
A. Benzoxazines
The multidrug regimen currently used to treat HIV infection includes three
drugs, a proteiase inhibitor, and two reverse transcriptase inhibitors. In
order to try to avoid the development of drug resistance, one of the latter
will consist of a modified nucleoside, while the second will be one of
several nonnucleosides inhibitors, such as those noted earlier in this
volume [capravirine (Chapter 5), etravirine (Chapter 6)]. The structure of
the benzoxazine inhibitor efavirenz ( 121 ), which differs significantly
from earlier agent points up to the wide structural divergence among this
class of antiviral agents. Acylation ofp-chloroaniline ( 112 ) with pivaloyl
chloride affords the corresponding amide ( 113 ). Treatment with butyl-
lithium followed by ethyltrifluoroacetate introduces the required trifluoro-
acetyl group ( 114 ). Acid hydrolysis then removes the pivaloyl group to
afford the free amine ( 115 ). This function is then protected from reagents
in the rest of the sequence by alkylation withp-methoxybenzyl bromide
( 116 ). The key reaction in the sequence involves stereospecific addition
of the cyclopropylacetylene moiety. Thus, addition of the lithium acetylide
from cyclopropylacetylene to the trifluoromethyl group in 117 in the pre-
sence of the substituted ephedrine derivative 118 proceeds with high enan-
tiomeric excess (ee). Reaction of the thus-obtained aminoalcohol ( 119 )
with phosgene closes the benzoxazine ring ( 120 ). The methoxybenzyl
176 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING