Sodium Carbonate → 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonyl chloride (0.19 g, 1.2 mmol, Preparation #4). After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.42 mL, 5.8 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then aqueous Na2CO3 (2 M, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. The reaction was heated at about 90° C. for about 3 days. The reaction was concentrated under reduced pressure to remove MeOH and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was separated and dried over anhydrous Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified over silica gel (12 g) using EtOAc as the eluent and then further purified by RP-HPLC (Table 2, Method b). The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN and the resulting precipitate was collected by vacuum filtration to afford 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z: 256 (M+H)+.

1. additionAfter the complete addition
2. customthe ice bath was removed
3. temperaturethe reaction was heated at about 90° C. for about 1 h
4. temperatureto cool to ambient temperature
5. temperatureThe reaction was heated at about 90° C. for about 3 days
6. concentrationThe reaction was concentrated under reduced pressure
7. customto remove MeOH
8. custompartitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL)
9. customThe organic layer was separated
10. dry with materialdried over anhydrous Na2SO4
11. concentrationthe solvent was concentrated under reduced pressure
12. customThe residue was purified over silica gel (12 g)
13. customfurther purified by RP-HPLC (Table 2, Method b)
14. additionThe combined product-containing fractions
15. concentrationwere concentrated under reduced pressure
16. customto remove the MeCN
17. filtrationthe resulting precipitate was collected by vacuum filtration

ORD-Eintrag

ord-55edf75d7dbf47338a164054fa417028

Quelldatensatz

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09365579B2