Organic Chemistry of Drug Synthesis. Volume 7

In a classic sequence for building a pyrimidine ring, the aniline ( 57 )is
condensed with cyanamide. Addition of the basic nitrogen to the nitrile in
the reagent leads to formation of the guanidine ( 58 ). Condensation of 58
with methyl ethyl acetoacetate results in formation of the pyrimidine
( 59 ); the residue of the carboxyl group appears as an enol oxygen ( 59 ;
R¼OH). Treatment of this intermediate with phosphorus oxychloride
replaces the enol oxygen by chlorine. Displacement of this last group by
the basic amine in other moiety ( 56 ) leads to the coupling product ( 61 ).
Thus, the sodium–potassium pump inhibitorrevaprazanis obtained.^9

NH 2

53

Ac 2 O

NH

PPA

N

O

NaBH 4

54 55

H 2 N

FH

2 NCN

NH

F

H 2 N

NH

(^5758)
O
OC 2 H 5
O
NH
N F
N
R
59 ; R = OH
60 ; R = Cl
NH
N F
N
N
NH
56
61

2. POCl 3

1.

A pyrimidine ring forms the nucleus for yet another nonnucleoside
reverse transcriptase inhibitor (NNRTI) active against HIV. This hetero-
cyclic ring is prepared in a manner analogous to that outlined above.
The starting guanidine ( 62 ) can be prepared by reaction of 4-cyanoaniline
with cyanamide. Condensation of 62 with ethyl malonate leads to the sub-
stituted pyrimidine 63 in a single step. The enolic hydroxyls are then

NC

HN NH 2

NH 2

62

C 2 H 5 O 2 C

C 2 H 5 O 2 C

HN

N

N

NC

OH

63 OH

POCl 3

HN

N

N

NC

Cl

64 Cl

Br 2

HN

N

N

NC

Cl

Cl

65

Br

H 3 C CH 3

CN

HN

N

N

NC

Cl

66

Br

HO

CH 3

H 3 C CN

O

H 3 C CH 3

CN

HN

N

N

NC

NH 2

67

Br

O NH 3

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