Organic Chemistry of Drug Synthesis. Volume 7

replaced by chlorine by reaction with phosphorus oxychloride. Treatment
of product 64 with bromine replaces the remaining hydrogen on the pyri-
midine ring by bromine ( 65 ). Reaction of intermediate 65 with the enolate
from 2,6-dimethyl-4-cyanophenol displaces one of the halogens forming
an ether linkage ( 66 ). The symmetrical nature of the pyrimidine ring
renders moot regiochemistry. Displacement of the remaining chlorine
with ammonia completes the synthesis ofetravirine( 67 ).^10
The structure of the relatively simple pyrimidoneemivirine( 71 ) might
suggest that this compound is a classical non nucleoside reverse transcrip-
tase inhibitor. Detailed studies have, however, shown that instead this com-
pound acts at the same site as other NNRTIs. Base-catalyzed alkylation of
the pyrimidine (also called a uracil) ( 68 ) with ethyl chloromethyl ether
perhaps surprisingly takes place at the nitrogen flanked by a single carbo-
nyl to yield 69. Reaction with a second equivalent of base, this time LDA,
followed by benzaldehyde results in addition of a benzyl group to the only
open-ring position. The reaction is then quenched with acetic anhydride to
afford the acetoxy derivative ( 70 ). Catalytic hydrogenation then removes
the acetoxy group to afford 71.^11

NH

NH

O

O

68

Cl O

N

NH

O

O

O

1. LDA


2. C 6 H 5 CH=O N

NH

O

O

O

AcO

3. Ac 2 O

69

70

H 2

N

NH

O

O

O

71

The efficacy and good tolerance of so-called statins has led to their
widespread use in the treatment of elevated serum cholesterol. These
agents act as a very early step in the endogenous synthesis of that
steroid. This initial stage comprises reduction of the activated carboxylic
acid group (COSCoA) (CoA is coenzyme A) in the glutaric acid derivative
hydroxymethylglutaryl CoA to an alcohol (CH 2 OH); the product, meval-
onic acid, then goes on to the isoprene equivalent, isopentenyl pyro-
phosphate, in several more steps. This pivotal reaction is catalyzed by an
enzyme hydroxymethylglutaryl CoA reductase (HMG–CoA); statins are
thus more correctly classed as HMG–CoA inhibitors. All approved inhibi-
tors feature a side chain that mimics the HMG–CoA substrate. The remain-
der of the structure of drugs varies widely ranging from the decalins found
in the first statins produced by fermentation to monocyclic heterocyclic
rings in some more of the recently introduced drugs. The synthesis of a
statin based on a pyrimidine ring begins with Knoevnagel condensation

2. COMPOUNDS WITH TWO HETEROATOMS 123