Methylamine → HCID 45111276, compound

A 2:1 mixture of 3,5-dibenzyl 6-methyl (6S)-4-isopropyl-6,7-dihydro-3H-imidazo[4,5-c]-pyridine-3,5,6(4H)-tricarboxylate and 5-benzyl 6-methyl (6S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5,6-dicarboxylate (mixture of 4S and 4R diastereomers; 600 mg, ˜1.20 mmol) was dissolved in DMF (6 mL) and methylamine (1.22 mL, 2 M in THF, 2.44 mmol) was added. The reaction mixture was split into 3 equal portions. The first reaction mixture was stirred at room temperature for 18 h. The second reaction mixture was heated at 60° C. for 4 h, methylamine (0.20 mL, 2 M in THF, 0.41 mmol) was added and the reaction mixture was heated under reflux at 80° C. for 18 h. The third reaction mixture was heated using a Biotage microwave (100° C., absorption high, pre-stirring 20 sec) for 20 min, methylamine (0.20 mL, 2 M in THF, 0.41 mmol) was added and the reaction mixture was heated using a Biotage microwave (120° C., absorption high, pre-stirring 20 sec) for 20 min. Methylamine (1.00 mL, 2 M in THF, 2.00 mmol) was added and the reaction mixture was heated using a Biotage microwave (160° C., absorption high, pre-stirring 20 sec) for 20 min. The 3 reaction mixtures were combined and the solvents were removed in vacuo. The residue was partitioned between EtOAc (30 mL) and sat aq NaHCO3 solution (30 mL). The organic layer was washed with sat aq NaHCO3 solution (30 mL), brine (30 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 40% to 90% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give 5-benzyl 6-methyl (4S,6S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5,6-dicarboxylate (46.2 mg, 2.7%) as a white solid.

1. customThe reaction mixture was split into 3 equal portions
2. customThe second reaction mixture
3. temperaturewas heated at 60° C. for 4 h
4. temperaturethe reaction mixture was heated
5. temperatureunder reflux at 80° C. for 18 h
6. customThe third reaction mixture
7. temperaturewas heated
8. customa Biotage microwave (100° C., absorption high, pre-stirring 20 sec) for 20 min
9. temperaturethe reaction mixture was heated
10. customa Biotage microwave (120° C., absorption high, pre-stirring 20 sec) for 20 min
11. temperaturethe reaction mixture was heated
12. customa Biotage microwave (160° C., absorption high, pre-stirring 20 sec) for 20 min
13. customThe 3 reaction mixtures
14. customthe solvents were removed in vacuo
15. customThe residue was partitioned between EtOAc (30 mL)
16. washThe organic layer was washed with sat aq NaHCO3 solution (30 mL), brine (30 mL)
17. dry with materialdried (MgSO4)
18. customthe solvents were removed in vacuo
19. customThe residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 40% to 90% (over 7 min)

ORD record

ord-be6d98bbc48b4991ae21c6679ab2888f

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08263616B2