Organic Chemistry of Drug Synthesis. Volume 7

product 74 , which contains the secondary amine required for coupling with
the other major fragment.
Synthesis of the second heterocyclic fragment begins with the conden-
sation of phenylglyoxal oxime ( 75 ) with guanidine to form the pyrazine
N-oxide ( 76 ). Treatment with triethylphosphine reduces the N-oxide func-
tion leading to pyrazine ( 77 ). The amino group is next treated with nitrous
acid and the resulting diazonium salt reacted with hydrogen bromide to
afford the brominated derivative ( 78 ). Reaction of 78 with ethyl thioglyco-
late in the presence of sodium carbonate arguably begins by displacement
of bromine by sulfur to form the transient thioether ( 79 ). Addition of the
enolate on carbon adjacent to the ester then attacks the cyano group to
form the fused thiophene ring 80. The newly formed amine on the thio-
phene ring is then converted to the corresponding isocyanate ( 81 ), by reac-
tion with phosgene.

O

NOH

75

H 2 N NH 2

NH

N

N

O

CN

NH 2

76

P(OC 2 H 5 ) 3

N

N CN

NH 2

77

HONO

HBr N

N CN

Br

N

N

S

NH 2

CO 2 C 2 H 5

N

N CN

HS

CO 2 C 2 H 5

S

CO 2 C 2 H 5

78

80 79

N

N

S

N=C=O

CO 2 C 2 H 5

81

COCl 2

Na 2 CO 3

There remains the task of joining together the two heterocyclic frag-
ments. To this end the free secondary amino group on the benzoxazine ( 74 )

N

N

S

O=C=N

C 2 H 5 O 2 C

81

O

OCH 3 NH

74

1.Br CN

2. Ni

O

OCH 3 N

NH 2

N

N

S

NH

C 2 H 5 O 2 C

O

OCH 3 N

HN

O

83

N

N

S

NH

N

O

O

O

OCH 3

N

84

82

226 POLYCYCLIC FUSED HETEROCYCLES