Organic Chemistry of Drug Synthesis. Volume 7

group for the next reaction. This last intermediate ( 180 ) is reacted with the
diaryl piperazine (181a) in the presence of base.
The thus formed phenoxide displaces the toluenesulfonate to form the
extended coupling product (181b). The nitro group is reduced to the cor-
responding amine. That function is then reacted with phenoxycarbonyl
chloride to give the phenoxy carbamate. Treatment with hydrazine displace
the phenoxide yielding the semicarbazone ( 182 ). Ethyl orthoformate
supplies the remaining carbon atom to form the triazolone ( 183 ). The
last step in the sequence comprises alkylation of the heterocyclic ring
with the chiral methoxymethyl protected 2,3-pentanediol 3-tosylate
( 184 ). Thus, the antifungal agentposaconazole( 185 ) is obtained.^28

F

F

N
N

N

O NO 2

181b

1. H 2


2. C 6 H 5 OCOCl


3. NH 2 NH 2
   182

184

NHNH 2

O

N NHN

O

TsO O O

N

N

O

OH

F

F

N

N

N

O O NN NH

F

F

N

N

N

O O N N

F

F

N

N

N

O O NN

183

185

O N N

N

Administration of cancer chemotherapeutic agents is more often than
not accompanied by serious bouts of nausea and vomiting. The serotonin
antagonists, such as ondansetron, were the first class of antiemetic drugs to
provide relief to patients undergoing chemotherapy. The involvement of
substance P in mediation of the emesis reflex offers another target in the
search for compounds for treating nausea. The demonstration that the
substance P related neurokinin hNK-1 is directly involved in that reflex
has led to the search for specific antagonists. The stereoselective synthesis
of the antagonistaprepitant( 200 ) begins with the preparation of chiral
p-fluorophenylglycine ( 190 ). Coupling of the phenylacetic ester ( 187 )
with the chiral auxiliary ( 186 ) affords the amide ( 188 ). The requisite

2. COMPOUNDS WITH TWO HETEROATOMS 105