Organic Chemistry of Drug Synthesis. Volume 7

epinephrine. Direct antagonism of the enzyme shuts down production of
that neurotransmitter. This achieves an effect on the cardiovascular
system more directly than do eithera-orb-blockers. The most immediate
effect is manifested as a decrease in blood pressure. The synthesis of the
specific hydroxylase inhibitornepicastat( 122 ) starts by reaction of aspar-
tic acid with trifluoroactetic anhydride. This reagent results in conversion
of the amine to its trifloroacetamide derivative and the acid to an anhydride
( 113 ). Reaction of this intermediate with 1,3-difluorobenzene in the pre-
sence of aluminum chloride gives the Friedel–Crafts acylation product
( 114 ). Catalytic hydrogenation then reduces the ketone to a methylene
group ( 115 ). A second acylation reaction, this time via the acid chloride
leads to the tertralone ( 116 ). The new carbonyl group is again reduced
by means of hydrogenation; saponification then removes the protecting tri-
fluoroacyl group to give the primary amine ( 117 ) as a single enantiomer.
Reaction of that amine with formaldehyde and potasium cyanide leads to
formation of what is essentially ana-aminonitrile, the nitrogen analogue
of a cyanohydrin. The amino group is then taken to a formamide by reac-
tion with butyl fomate. Formylation of the carbon adjacent to the nitrile by
means of ethyl formate and sodium ethoxide puts into place the last carbon
for the imidazole ring ( 120 ). Reaction of this last compound as its enolate
with thiocyanate forms the cyclic thiourea ( 121 ). Catalytic hydrogenation
serves to reduce the nitrile to the corresponding amino-methylene deriva-
tive and thus 122.^18

H 2 OC CO^2 H

112 NH^2

(CF 3 C0) 2 CO OC CO^2 H

NHCOCF 22

CO

F

F

F

F

113 AlCl^3 HO^2 C

NHCOCF 3

O

F

FHO^2 C

NHCOCF 3

1. PCl 5


2. AlCl 3
   F

F

NHCOCF 3

O

F

F

NH 2

(^114115)
117 116
H 2

1. H 2
   NaCN 2. NaOH

F

NH

NC

F

N

NC

CHOHCO 2 Bu

119 118

F

N

NC

CHO

HCO 2 C 2 H 5

NaOC 2 H 5

OC 2 H 5

120

KSCN

F F

F

F

N

F NC

NH

S

121

F

N

F NH

S

(^122) NH 2
H 2
CH 2 =O
Collagenase enzymes are intimately involved in the destruction of car-
tilage that accompanies rheumatoid arthritis. Considerable attention has as

2. COMPOUNDS WITH TWO HETEROATOMS 97