the product from formation of an imine from each aldehyde ( 66 ).
Replacing the ester with an amide by ester interchange with methylamine
completes the synthesis ofregadenoson( 67 ).^10
N
N NNOHH 2 N
HO OHO OH
60- Ac 2 O
- POCl 3 CH 2 l 2
N
N NNClH 2 NCH 3 CO (^2) O
HO OH
61
C 5 H 11 ONO N
N N
N
Cl
I
CH 3 CO (^2) O CH 3 CO 2
HO OH
62
NH 3 N
N N
N
NH 2
I
O
HO OH
63
N
N N
N
NH 2
NH
O
HO OH
64
H 2 NNH2
H 2 N
CH=O
C 2 H 5 O 2 C CH=O
65
N
N N
N
NH 2 NH 2
NH 2
CH 3 CO (^2) O
HO OH
66
N
CH N
3 NH 2
N
N N
N
CH 3 CO (^2) O
HO OH
67
N
N
O
OC 2 H 5
O
CH 3 CO 2
One of the most fruitful approaches for designing antiviral compounds
comprises administration of false substrates that will halt replication of the
viruses. Such agents will bring replication to a stop in the event they are
mistaken for the real thing. This strategy was validated some decades
ago by the antiviral agent acyclovir in which the sugar moiety is replaced
by an open-chain surrogate. Phosphorylation comprises one of the first
steps in incorporation of a nucleoside into DNA or RNA. Replacing the
phosphate by an analogous function that is mistakenly taken up by the
virus, but cannot be further processed, comprises yet another strategy for
halting viral replication. The HIV reverse transcriptase inhibitortenofovir
( 78 ), combines both those strategies in a single molecule. As a first step,
hydroxy ester 68 is protected by reaction with THP to form the correspond-
ing ether ( 69 ). The ester function is the reduced to the alcohol ( 70 )by
means of Selectride. The newly formed alcohol function is then activated
toward displacement by conversion to its tosylate ( 71 ). Reaction of 71 with
adenine ( 72 ) attaches the much abbreviated side chain to the five-
membered ring ( 73 ). The exocyclic amine function is then protected
as its benzamide ( 74 ) by means of benzoyl chloride and the THP
group removed with aqueous acid. The alkoxide from reaction of this
last intermediate ( 75 ) with sodium hydride is next alkylated with the
tosyl derivative of methyleneisopropyl phosphate ( 76 ) to afford the
methylene phosphoryl product ( 77 ). Removal of the protecting groups
completes the synthesis ( 78 ).^11
- COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 197