Oxonium, trimethyl-, tetrafluoroborate(1-) (1:1) → 7-[(3-Chloro-2-methylphenyl)carbonyl]-3-(5-methyl-1,3-thiazol-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine

4-[(3-Chloro-2-methylphenyl)carbonyl]-2-piperazinone (I131)(250 mg, 0.989 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (185 mg, 1.187 mmol) and stirring for 16 hours at RT under argon before adding 5-methyl-1,3-thiazole-4-carbohydrazide (I123) (233 mg, 1.484 mmol) and stirring for a further 3 hours. DCM was removed by evaporation and the residue was dissolved in 1-butanol (3.00 mL) before heating at 110° C. for 4 hours then cooled to RT overnight. The reaction was worked up by diluting with DCM (50 ml) and washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), the combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford a pale yellow cloudy gum as crude product. The product was purified on 50 g Isolera column, eluting with DCM (3CV) then 0-10% MeOH/DCM over 10CV. The desired fractions were isolated, the solvent evaporated and the residue was further purified by MDAP (formic acid method). The desired fraction was identified and the solvent evaporated to afford a white foam of desired product in 130 mg.

1. stirringstirring for a further 3 hours
2. customDCM was removed by evaporation
3. dissolutionthe residue was dissolved in 1-butanol (3.00 mL)
4. temperaturebefore heating at 110° C. for 4 hours
5. temperaturethen cooled to RT overnight
6. additionby diluting with DCM (50 ml)
7. washwashing with saturated sodium bicarbonate solution (50 ml)
8. extractionThe aqueous layer was extracted with DCM (2×30 ml)
9. washthe combined extracts were washed with brine (30 ml)
10. dry with materialdried (MgSO4)
11. filtrationfiltered
12. customevaporated
13. customto afford a pale yellow cloudy gum as crude product
14. customThe product was purified on 50 g Isolera column
15. washeluting with DCM (3CV)
16. customThe desired fractions were isolated
17. customthe solvent evaporated
18. customthe residue was further purified by MDAP (formic acid method)
19. customthe solvent evaporated

ORD record

ord-c52de83275bc4bc78f16fdf39dbdc99e

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501946B2