Formaldehyde → N-((2R,4R)-1-methyl-2-(6-methyl-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Temperature

65 °C

The (2R,4R)-tert-butyl 2-((2-amino-4-methylphenyl)carbamoyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate (4.8 g, 9.4 mmol) was dissolved in acetic acid (10 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Then TFA (10 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and did next reaction without further purification. 37% formaldehyde solution (3.5 mL, 47 mmol) in water was added to a solution of the residue in methanol (50 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (29 mL) was added carefully at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then solvent was evaporated in vacuum. Saturated sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL) were added and the mixture was stirred about 30 minutes. The organic layer was separated, dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep 120 g, silica gel packed) with CH3OH/CH2Cl2 from 2%-6-8% to give the title compound as an off-white solid 3.0 g (78%). LC-MS: 407.3, 405.3 (t=1.2 min).

1. concentrationThe reaction mixture was concentrated under reduced pressure
2. customto remove acetic acid
3. additionThen TFA (10 mL) was added to the residue
4. stirringThe resulting solution was stirred at room temperature for 2 hours
5. concentrationThe reaction mixture was concentrated
6. customto remove TFA
7. customreaction
8. customwithout further purification
9. stirringthe reaction mixture was stirred at room temperature for 1 hour
10. stirringThe reaction mixture was stirred at room temperature for 18 hours
11. customsolvent was evaporated in vacuum
12. additionSaturated sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL) were added
13. stirringthe mixture was stirred about 30 minutes
14. customThe organic layer was separated
15. dry with materialdried over MgSO4
16. concentrationconcentrated
17. customProduct was purified by Companion (ReadySep 120 g, silica gel packed) with CH3OH/CH2Cl2 from 2%-6-8%

ORD record

ord-8870ce4ab3944ab29d61d1c30f0877b9

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08148401B2