Organic Chemistry of Drug Synthesis. Volume 7

NH

O

Cl

O

O

190

+ H^2 N

F

Br

191

Cl NH 2

O

NH

F

Br

192

CDI

Cl NH

O

N

F

O Br

193

Cl N

O

N

F

O Br

1. BrCH 2 CO 2 C 2 H 5
   2. NaOH

CO 2 H

194

Fluid accumulation is one of the graver consequence of congestive heart
failure as this excess blood volume places additional strain on the weak-
ening heart. The hormone vasopressin also known as antidiuretic
hormone contributes to this effect. Though diuretics are often used to
decrease this the excess fluid these drugs often upset the balance of elec-
trolytes in the remaining fluid can thus adversely affect kidney function.
Thiazides are, for example, well known to cause excretion of potassium.
A recently developed non-peptide vasopressin antagonist has shown prom-
ising initial activity in relieving heart failure associated fluid retention
without an effect on electrolyte balance. Construction of the benzapine
moiety begins with esterification of anthranilic acid ( 195 ) followed by
reduction of the nitro group with stannous chloride ( 196 ). The aniline nitro-
gen is then converted top-toluenesulfonamide ( 197 ). Reaction of 197 with
ethylv-chlorobutyrate in the presence of potassium carbonate then gives
the alkylation product 198. Potassiumtert-butoxide-catalyzed Claisen con-
densation of this diester leads to azepinone 200 as a mixture of methyl and
ethyl esters resulting from alternate cyclization routes. Strong acid leads to
the transient ketoacid, which the decarboxylates; the toluenesulfonyl group
is lost under reaction conditions to afford the azepinone ( 201 ). This last
intermediate is then acylated with the benzoyl chloride 202 to afford
amide 203. Catalytic reduction of the nitro group proceeds to the aniline
( 204 ). The chain is next extended by acylation of the newly formed
amine with o-toluyl choride ( 205 ) to give 206. Reduction of

2. COMPOUNDS WITH TWO HETEROATOMS 185