1.2.3- Triazolo pyrazines

Another exemplar of the power of multi-step library synthesis is the optimisation of a PDE2 inhibitor HTS hit (Scheme 18.36). The HTS hit itself was derived from a library that was synthesised to enrich the Pfizer screening collection. Key steps in the library synthesis involved reaction of the commercial dichloro pyrazine H with a range of alcohols, followed by reaction of the intermediate chloroalkyoxy pyrazine with hydrazine. Finally, the hydrazine pyridazine I was reacted with a number of aldehydes under oxidative conditions to form the triazolo pyrazine derivatives. This library allowed the project team to find key SAR directions for improvinbg selectivity vs. other PDEs. ... 

In [l,2,4]triazolo[4,3-a]pyrazine (174) bromination took place at the 5-position rather than in the triazole ring (77JOC4197). It was not possible to convert the 3-hydroxy derivative into the 3-chloro analogue (68JHC485). The isomeric [1,5-a] compound (175) was also brominated at C-5 (74TL4539), whereas its 7-oxide gave the 8-chloro derivative under Meisenheimer conditions [80JCS(P1)506]. 

Vercek and co-workers described an effective approach to some 3-cyano-4-amino[l,2,3]triazolo[l,5-tf]pyrazines starting from the N-substituted triazole derivatives 396 <2002H(56)353>. This compound when treated either with acetic acid or triethylamine gave rise to the ring-closed products 397 in acceptable yield (55-66%). 

The preparation of biologically active [l,2,4]triazolo[l,5- ]pyrazines has been reported recently. The reaction routes are shown in Scheme 50. Dowling et al. reported <2005BML4809> the synthesis of aryl-substituted derivatives 411. The first step was the transformation of the 2-aminopyrazine compound 409 to an amidine 410, which was subjected... 

Relatively few new papers have appeared on synthetic procedures for the title ring system. Some of these follow established methodologies. Thus, three reports appeared where 2-hydrazinopyrazines - or their derivatives - were subjected to ring closure to give [l,2,4]triazolo[4,3- ]pyrazines. These products - with yields and references - are shown in Table 14. 

Table 14 [1,2,4]Triazolo[4,3-a]pyrazines prepared from 2-hydrazinopyrazines or their derivatives Entry Product Yield (%) Reference...

In connection with the synthesis of cytohalasin B, a pyrrole derivative 13 was prepared from methyl (5)-3-aminophenylbutyrate (78JA7775). In connection with the synthesis of l,2,4-triazolo[4,3-a]pyrazine derivatives with human Renin inhibitor activity, a /3,y-diamino acid derivative was transformed into a pyrrolidin-2-one (91JMC151). 

Aminotriazoles which are appropriately substituted at the C(5)-position are important intermediates for the synthesis of 8-azapurines. These reactions have been reviewed <86AHC(39)ll7>. The pharmaceutically useful acyclonucleosides bearing 1,2,3-triazolines and 8-azapurines have been synthesized <888879). 4,5-Diaminotriazoles react with 1,2-dicarbonyl reagents to give 1,2,3-triazolo[4,5- )]pyrazines. 4,5-Diamino-2-phenyltriazole and sulfur monochloride afford the triazolo[4,5-c][l,2,5]thiadiazole (855) <86AHC(40)129>. The synthesis of triazolopyridines from triazoles has been described in a review <83AHC(34)79>. For further applications of substituted triazoles in preparations of complex heterocycles, see Section 4.01.4. 

An example of this is the story of the process development of sitagliptin, (R)-3-amino-l-[3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, an active ingredient in Januvia and... 

Ring contractions of six- or seven-membered fused systems have sometimes been used to synthesize azapentalenes. Taylor et a/.158 found that triazolo[4,3-a]pyrazines (164) rearrange in acid to imidazotriazoles 165 following initial fission of the six-membered ring at the point shown (164). The kinetics,58b of this reaction have revealed the intermediacy of covalently hydrated species. 

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