Diisopropylethylamine → 7-[(3,4-Difluoro-2-methylphenyl)carbonyl]-3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine

3,4-Difluoro-2-methylbenzoic acid (I68)(124 mg, 0.720 mmol) was dissolved in dry N,N-dimethylformamide (DMF) (4.7 mL) before treating with HATU (274 mg, 0.720 mmol) and DIPEA (0.252 mL, 1.441 mmol) and stirring for 15 mins at RT, under argon before adding 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115)(100 mg, 0.480 mmol) and stirring for a further 18 hours. LCMS confirmed that the desired material was present and that no start material was left. The reaction was worked up by diluting with DCM (50 ml), washing with water (50 ml). The aqueous layer was extracted with DCM (2×30 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO4), filtered and evaporated to afford a pale pink gum. The product was purified on a SNAP 50 g cartridge, eluting with 0-10% MeOH in DCM, the desired fractions were collected and the solvent was evaporated to afford a dark orange gum. Due to presence of residual DMF the crude gum product was diluted with DCM (30 ml), washed with brine (2×20 ml), dried (Na2SO4), filtered and evaporated to afford an orange foam. The foam triturated with n-hexane to afford a pale orange solid. Liquers were removed and the residue was triturated again with n-Hexane. Liquers were removed and the solid was dried overnight in the vac oven at 40° C. to afford desired product in 146 mg as a pale orange solid.

1. stirringstirring for a further 18 hours
2. waitwas left
3. washwashing with water (50 ml)
4. extractionThe aqueous layer was extracted with DCM (2×30 ml)
5. washThe combined extracts were washed with brine (30 ml)
6. dry with materialdried (Na2SO4)
7. filtrationfiltered
8. customevaporated
9. customto afford a pale pink gum
10. customThe product was purified on a SNAP 50 g cartridge
11. washeluting with 0-10% MeOH in DCM
12. customthe desired fractions were collected
13. customthe solvent was evaporated
14. customto afford a dark orange gum
15. washwashed with brine (2×20 ml)
16. dry with materialdried (Na2SO4)
17. filtrationfiltered
18. customevaporated
19. customto afford an orange foam
20. customThe foam triturated with n-hexane
21. customto afford a pale orange solid
22. customLiquers were removed
23. customthe residue was triturated again with n-Hexane
24. customLiquers were removed
25. customthe solid was dried overnight in the vac oven at 40° C.

ORD record

ord-6312d175757f445597e0b16d1c479491

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501946B2