Organic Chemistry of Drug Synthesis. Volume 7

N

N

OCH 3

OCH 3 F

F

F

Br

F

F F

154

155

N

N

OCH 3

OCH 3

1. H 3 O+
   2.t-BOC 2 O
   F

F

F

OH

NHt-BOC

NHt-BOC NH t-BOC NHt-BOC

NHt-BOC

O

156

3. LiOH
   1.iBuOCOCl
   2. CH 2 N 2

F

F

F

O

PhCO 2 Ag

N 2

157

158

F

F

F

CO 2 CH 3

159

CH 3 OH

LiOH

F

F

F

CO 2 H

160

153

N N

N

CF 3

F

F

F

N

161

HCl

N N

N

CF 3

F

F

F

NH 2

N

162

O

O

The majority of nucleoside antiviral agents, as noted previously,
inhibit the production of new virions by acting as false substrates for
the enzymes that synthesize viral DNA or RNA. The nucleoside-like
compound,isatoribine( 170 ) has shown activity against hepatitis C, a
viral infection unusually refractory to treatment. This agent interestingly
owes its efficacy to its stimulation of the immune system rather than to
direct antiviral action. Condensation of the substituted malonate ( 162 )
(obtained by alkylation of 2-bromomalonate with 2-trimethylsilyl ethyl-
mercaptan) with guanidine affords the pyrimidine ( 163 ). The function at
the 4-position is then converted to the corresponding halide by reaction
with phosphorus oxychloride to yield 164. Addition–elimination of the
pyrimidine hydroxyl with the aminated sugar ( 165 ) adds the requisite
saccharide moiety to the compound 166. The bridging amino group is
next acylated with ethyl chloroformate to yield 167. Treatment of 167
with tributylammonium fluoride leads to loss of the silyl group on the
terminus of the ethyl mercaptide. The chain on sulfur then collapses
to leave behind an anion on that atom. This ion then displaces the eth-
oxide from the carbamate on the proximate nitrogen in effect closing the
thiazolone ring; the silyl protecting group on the sugar also cleaves
under reaction conditions to yield the free carbinol ( 168 ). The chlorine
atom at the 4 position, which has served to protect that function over the
preceding steps, is then replaced with sodium methoxide to form the
methyl ether ( 169 ). Trimethyl silyl iodide then cleaves that ether to

1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 207