Organic Chemistry of Drug Synthesis. Volume 7

The peptide hormone, glucagon-like peptide (GLP-1), which is
released in response to intake of food, regulates insulin levels. The
hormone, in the normal course of events, exerts only momentary
activity as it is quickly inactivated after its release by a dipeptidal pep-
tidase (DPP). Inhibitors of that degrading enzyme should thus lead to
persistent levels of GLP-1. The search for small molecule inhibitors
of DPP that prolong the action of GLP-1 has consequently been the
focus of research for finding alternate methods for controlling Type 2
diabetes. Construction of the heterocyclic nucleus ( 153 )beginswith
the displacement of chlorine in pyrazine ( 149 ) with hydrazine to
afford 150. Acylation with trifluoroacetic anhydride proceeds on the
more basic terminal nitrogen to afford the trifluoroacetohydrazide
( 151 ). Treatment of this intermediate with polyphosphoric acid leads
the enol form of the amide to undergo addition–elimination with the
pyrazine nitrogen and to form the new fused ring ( 152 ). Catalytic
hydrogenation proceeds to selectively reduce the six-membered ring
to afford the triazolopyrazine ( 153 ).

N

N

149

Cl

H 2 NNH 2 N

N

150

HN

NH 2 (CF 3 CO) 2 O N

N

151

HN

NH

O CF 3

PPA

N

N NN

CF 3

152

H 2

N

HN NN

CF 3

153

In the other arm of the convergent scheme, the bis(lactam) enol ether
( 154 ) can be viewed as a latent chiral carboxyl group since the transan-
nular isopropyl group will transfer its chirality across the ring to a new
entering moiety. Thus, alkylation of the enolate from 154 with the tri-
fluorobenzyl chloride ( 155 )yields( 156 ) as virtually a single enantio-
mer. Methanolysis of the product followed by bis-t-BOC affords the
correspondingt-BOC protected amino acid. Saponification then yields
the carboxylic acid 157. This product is next subjected to Arndt–
Eistert homologation. The carboxylate is first converted to its acid
chloride withtert-butyl chloroformate. This intermediate affords diazo-
ketone 158 with diazomethane. Treatment with silver benzoate causes
this reactive species to rearrange to the homologated ester ( 159 ). The
acid ( 160 ) obtained on saponification is then coupled in the presence
of a diimide with the heterocyclic nucleus 153 to afford the amine
161. Removal of the t-BOC protecting group from 105 with strong
acid completes the synthesis ofsitagliptan( 162 ).^23

206 BICYCLIC FUSED HETEROCYCLES