Organic Chemistry of Drug Synthesis. Volume 7

for agents that decrease platelet aggregability: Widely used clopidogrel, for
example, blocks adenosine diphosphate receptors on platelets, newer can-
didates, such as the “gartans” (Chapter 1), act further down the line by inhi-
biting fibrinogen. The compound at handapafant( 67 ) antagonizes the
action of the platelet activating factor (PAF), a substance that not only
induces platelet aggregation, but is a factor in inflammatory processes
and hypersensitivity. Reaction of theb-ketoaldehyde, diester 58 with the
benzoyl nitrile ( 59 ) in the presence of sulfur leads to formation of the amino-
thiophene ( 60 ). Overlooking the diester for the moment, the reaction can be
rationalized for bookkeeping purposes by assuming condensation of the
aldehyde with the activated ketonitrile methylene group, conversion of
the ketone to a thioketone and addition of that to the cyano group as its
enolate, though not necessarily in that order. Heating the product in
strong acid cause the diester in the product to decarboxylate. The resulting
acid is then reesterified with methanol ( 61 ). Construction of the diazepine
ring starts by alkylation of the amino group with bromoacetamide in the
presence of base to afford 62. Strong acid, for example, polyphosphoric
acid, the causes the side-chain amide nitrogen to react with the ketone to
form a cyclic imine affording 63. The ester grouping is then restored and

O

CO 2 C 2 H 5

58

O Cl

59

S 8

S

O

CO 2 C 2 H 5

H 2 N

C 2 H 5 O 2 C

CO 2 C 2 H 5

Cl

O = HC NC

60

1. HCl
   S
   H 2 N O

CO 2 CH 3

Cl

61

2. CH 3 OH

H 2 NOC Br

S

HN O

CO 2 CH 3

Cl

O

NH 2

62

S PPA

CO 2 H

Cl

63

HN N

O

S 2. P 4 S 10

CO 2 CH 3

Cl

64

HN N

S

S

CO 2 CH 3

HN N Cl

N

+

CH 3 CH(OC 2 H 5 ) 3

H 2 N

S

CO 2 CH 3

Cl

66

NN

N N

H 3 C

1. CH 3 OH

S

Cl

67

N N

N N

H 3 C

N

O

HN O

O

65

N 2 H 4

224 POLYCYCLIC FUSED HETEROCYCLES