Triazolopyrazine Series

A three necked round bottomed flask was fitted with a reflux condenser and two stoppers. The hydrazone product (EO 11-1), 0.1547 g was added to the flask. Potassium carbonate (0.2209 g) was also added and the flask was flushed woth nitroge. Toluene (1.238 ml) and product from EO 9-1 (0.25 g) wewre added, followed by Pd(dppf)CL₂.CH₂Cl₂ (0.0040 g). The flask was flushed again with nitrogen amd the reaction mixture was heated to 100^oc for 2.5 houirs. The reaction misture was then cooled to room temperature at which point water (0.572 ml) was added to solubulise the inorganic by products. The mixture was stirred at room temperature for 15 minutes and then filtered through a filter funne. The resulting wetcake was rinsed with tolune (3 x 0.286 ml). ir drying afforeded the coupled product

4-formylbenzonitrile (1.31 g) wqaas added to a solutionof 100% hydrazine hydrate ( 4.9 ml) in ethanol (10 ml). the reaxction was refuxed for 3 hrs at 105^oc and cooled to room temperature. No percipitate was produced and the EtOH was removed under vacuum to yield a thick yellow liquid ( 5.19 g) Nmr was derived. (EO 11-1 1H NMR)

Additional EtOH was then added (8 ml) and placed under the solution was placed under the rotary evaporator to produce yellow crystals. (1.67 g) NMR was derived (EO 11-1b 1H NMR) TLC was also attained using 100% EtoAc.

Methyl 6-chloro-2-pyrazinecarboxylate (1.03 g, 10.3 mmol) from sample 3/4 of EO 6-2 was dissolved in EtOH (14.5 mL). 2M NaOH (14.5 mL) was added, and the reaction stirred at ambient temperature for 2 h. The reaction mixture was acidified to pH3 with 2M HCl (aq). The mixture was then diluted with water (86.80 mL) and extracted with EtOAc (4 x 57.87 mL). The organic extracts were combined, washed with brine (57.87 ml) dried over Na₂SO₄, filtered and concentrated under vacuum to provide the title compound as a white solid (0.63 g, xx %).  NMR was derived.

Product from EO 9-1 (0.92 g) was vigorously stirred in ethanol (10 mL) and hydrazine hydrate (0.33 mL) was added. The resulting mixture was heated at 105˚C for 60 hrs.

After completion, the  solvent was removed under vacuum to yield a crude orange liquid (3.13 g). NMR data (EO 10.1 x 4 NMR)

Work up on the product was carried out involving addition of 0.1 M HCl (0.9 ml) to the product (0.9 ml) No seperation occured. EtOAc (5 ml) wqas then added. the bottom HCl layer was discarded and the top EtOAc layer washed with 5% LiCl (4 x 3 ml), disgarding the bottom LiCL layer with each wash. top layer was then collected and placed under vacuum to remove EtOAc. NMR was derived for the work up product  (EO 10.1 b x 4)

6-chloropyrazine-2-carboxylic Acid (i.e. EO 7-2, 0.1 g) in DMF (5 ml) was added to EDC couping reagent (0.108 g) and 1- hydroxybenzotriazole (0.1063 g) and stirred for 30 minutes. 4- aminopyridine (0.065 g)was then added, followed by N,N- Diisopropylethylamine (0.23 ml). The reaction was stirred for 22 hours, after which time it was diluted with H₂O. The resultant solution as opposed to siolid was dried under high vacuum to provide the liquid product (2.51g) NMR was derived showed significant amount of dMF was still present (EO 9-1 X 4).

work up on the product was carried out involving addition of 0.1 M HCl (1.3 ml) to the product (1.3 ml) No seperation occured. EtOAc (5 ml) wqas then added. the bottom HCl layer was discarded and the top EtOAc layer washed with 5% LiCl (4 x 3 ml), disgarding the bottom LiCL layer with each wash. top layer was then collected and placed under vacuum to remove EtOAc. NMR was derived for the work up product  (EO 9.1b x 4)