1.2.4- Triazolo pyrazine 7-oxide

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]. 

The l,2-diamino-4-methylthiazole 73 with phosgeniminium chloride gives the thiazolo[3,2-A [l,2,4]triazole derivative 74 (Scheme 45) <1973AGE806>. Reaction of the sulfimide 75 with nitrile oxides forms [l,2,4]triazolo[l,5- ] pyridine 3-oxides 76 in good yields (Scheme 46). This method is applicable to analogous pyrimidines and pyrazines <1976J(P1)2166, 1978BCJ563>. 

Hydrazinopyrazine 4-oxide (204) gave l,2,4-triazolo[4,3-a]pyrazine 7-oxide (206) by loss of AcOH from the unisolated intermediate (205) [neat... 

Heating [l,2,3]triazolo[l,5-a]pyrazine (33) in deuterium oxide caused three protons to be exchanged and for (251) to result. NMR evidence indicated that H-5 was the first one exchanged followed by H-1 and then H-8 (78HCA1755). 

Phenyl-[l,2,4]triazolo[l,5-(2]pyrazines have been prepared by the oxidative ring closure of iV(2)-pyrazinylbenzamldines (344) as shown in Scheme 60. The benzamidines were synthesized from 2-aminopyrazines and benzonitrile, a reaction that failed with aliphatic nitriles (64JOC2542). 

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