process of infection. Synthesis of this agent starts by protection of the amino
group in the bridged bicyclic amine ( 201 ). The carbonyl group at the other
end of the molecule is then converted to its oxime. Treatment of this inter-
mediate with sodium in alcohol reduces that group to a primary amine ( 204 ).
Construction of the triazole ring first involves acylation of the aminewith the
acid chloride from isobutyric acid to form the isobutyramide ( 205 ). Reaction
of 205 with phosphorus oxychloride convertsthe amide into the correspond-
ing chlorinated imine ( 206 ). Treatment with acylhydrazide leads to
addition–elimination of the basic hydrazide nitrogen to the imino chloride
and thus formation of the imino–amide ( 207 ). Heating in the presence of
acid leads to reaction of the imino nitrogen with the carbonyl group. This
closes the ring and affords the triazole ( 208 ). Catalytic reduction removes
the benzyl protecting group ummasking the basic ring nitrogen ( 209 ). In a
converging scheme, the ester in the peptide-like fragment ( 210 )is
reduced to afford aldehyde 211. Reductive amination of 211 with amine
209 and sodium triacetoxy borohydride leads to the coupled product 212.^30
A substituted 1,2,3-triazole ring provides the pharmacophore for an anti-
epileptic drug. Reaction of the 2,5-difluorobenzyl bromide ( 213 ) with
sodium azide leads to displacement of the benzylic halogen and formation
of azide 214. Treatment of 214 with propargylic acid leads to a 2þ 3
cycloaddition reaction and thus formation of the 1,2,3-triazine ring ( 215 ).
The carboxylic acid is then converted to its amide via the acid chloride.
Thus, the antiepileptic agentrufinamide( 216 ) is obtained.^31
F FBr213NaN 3 F FN214NNH
CO 2 H F FN215NNCO 2 HFN216NNCONH 2- SO 2 Cl
- NH 3
As noted earlier, protein kinases play a pivotal role in cell proliferation.
Inhibitors of these enzymes show promise as antitumor agents particularly,
those that show preference for malignant cells. The kinase inhibitor
mubritinib( 221 ) is currently being evaluated as a drug for treating breast
cancer. The first step in the convergent synthesis comprises displacement
of a leaving group, such as methanesulfonate, from a suitably protected
phenol ( 217 ) by 1,2,3-triazine proper. Removal of the protecting group
leads to the free phenol ( 218 ). Preparation of the second moiety involves
reaction of one of the classical methods for forming of an oxazole: reaction
108 FIVE-MEMBERED HETEROCYCLES