Organic Chemistry of Drug Synthesis. Volume 7

carbamate. The nitrile group is then transformed to a tetrazole by reaction
with sodium azide in the presence of aluminum chloride, one of the stan-
dard procedures for building that ring. The surrogate acid is then alkylated
with ethyl iodide to afford 228. Treatment with acid then removes the
carbamate on the ring nitrogen ( 229 ). The methyl group on the piperidine
ring is restored by reaction with formaldehyde and formic acid, under stan-
dard Clark–Eshweiler conditions. Thus, the muscarinic agonist 230 is
obtained.^33

N

CH 3

CO 2 CH 3

222

N

CN CH

3 I

N

CN

CH 3

+

(^223224)
NaBH 4
N
CN
CH 3
225
ClCO 2 C 2 H 5
N
CN
CO 2 C 2 H 5
NaN 3
AlCl 3
N
CO 2 C 2 H 5
226
N
NH
N N
227
C 2 H 5 I
N NaOH
CO 2 C 2 H 5
N
N
N N
228
CH 2 CH 3
HBr
NH
N
N
N N
229
CH 2 CH 3
N
N
N
N N
230
CH 2 CH 3
CH 3
K 2 CO 3
HCO 2 H
CH 2 =O
A neurokinin inhibitor whose structure differs markedly from aprepitant
( 200 ) incorporates a substituted tetrazole ring. The synthesis of the
tetrazole-containing moiety ofvofopitant( 241 ) start by acylation of sub-
stituted aniline 231 with trifluoroacetyl chloride to afford the amide ( 232 ).
Reaction of that under Mitsonobu conditions leads to the enol chloride
( 233 ). Treatment of 233 with sodium azide probablty starts with addition–
elimination of azide ion; this undergoes internal 1,3-cycloaddition
to form the tetrazole ring. Catalytic hydrogenation then removes the benzyl
C 6 H 5 CH 2 O
NH 2
231
CF 3 COCl
C 6 H 5 CH 2 O
NH
232
O
CF 3 CCl 4
(C 6 H 5 ) 3 P
C 6 H 5 CH 2 O
N
233
Cl
CF 3
NaN 3
C 6 H 5 CH 2 O
N
NN
N
CF 3
H^234
2
HO
N
NN
N
CF 3
235
HO
N
NN
N
CF 3
236
H 3 CO
O HC N
NN
N
CF 3
237
HMTA
O=HC AcOH
CH 3 I
K 2 CO 3
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