Organic Chemistry of Drug Synthesis. Volume 7

Reaction of this intermediate with base leads the anion of the newly
revealed hydroxyl group to attack with the carboxylate in what amounts
to an internal transesterification. This step forms the cyclic ester and thus
the requisite pyranone ring ( 50 ). Catalytic hydrogenation of 50 results in
reduction of the nitro group to yield 51. Acylation of the newly formed
amine with 5-trifluoromethylpyridinium-2-sulfonyl chloride affords 52.^8

O=HC

NO 2

CH 3 O 2 C

CH 3 O 2 C

Base NO

2

CH 3 O 2 C

CO 2 CH 3

44 45

(C 2 H 5 ) 2 Zn

CuBr

NO 2

CH 3 O 2 C

CO 2 CH 3

46

NO 2

CO 2 CH 3

47

1. HCl


2. CH 3 OH


3. Resolve

O

43

O

NO 2

CO 2 CH 3

ROCHO ROCH^2

2

OH

48

1. PCC
   NO 2 2. H+

OHCO^2 CH^3

O

49

NaOH

NO 2

O

OH

50

O

H 2

NH 2

O

OH

51

O O HN

OH

52

O

SO 2

N

CF 3

2. COMPOUNDS WITH TWO HETEROATOMS

A. Pyrimidines

The structures of all currently approved gastric acid secretion inhibitors that
act as inhibitors of the sodium–potassium pump consists of variously sub-
stituted pyridylsulfonyl-benzimidazoles. A structurally very distinct com-
pound based on a pyrimidine moiety has much the same activity as the
benzimidazole-based drugs. In yet another convergent synthesis, reaction
of b-phenethylamine ( 53 ) with acetic anhydride affords amide 54.
Treatment with polyphosphoric acid (PPA) then leads to ring closure to
form the dihydroisoquinoline ( 55 ). Sodium borohydride then reduces the
enamine function to afford fragment 56.

2. COMPOUNDS WITH TWO HETEROATOMS 121