Reaction #42138

Reaction equation

4-(N-tert-butoxycarbonylaminomethyl)aniline

3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid

HATU

DIPEA

→

title intermediate

Yield 94.0%

Biphenyl-2-ylcarbamic Acid 1-[2-(4-Aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl Ester

Yield 94.0%

Solvents

TFA DCM

DMF

Conditions

Workup

1. 1
   Otherthe solvent was removed under reduced pressure
2. 2
   workup.DISSOLUTIONThe resulting residue was dissolved in DCM (20 mL)
3. 3
   Washwashed with saturated aqueous sodium bicarbonate solution (10 mL)
4. 4
   DryingThe organic phase was then dried over MgSO4
5. 5
   Otherthe solvent was removed under reduced pressure
6. 6
   OtherThe crude product was purified by flash chromatography (5-10% MeOH/DCM)
7. 7
   Otherto give a solid, which
8. 8
   workup.STIRRINGstirred at room temperature for 2 hours
9. 9
   OtherThe solvent was then removed under reduced pressure
10. 10
    workup.DISSOLUTIONthe crude residue was dissolved in DCM (30 mL)
11. 11
    Washwashed with 1N NaOH (15 mL)
12. 12
    OtherThe organic phase was separated
13. 13
    Dryingdried over MgSO4
14. 14
    Filtrationfiltered
15. 15
    Otherthe solvent was removed under reduced pressure

Procedure

To a stirred solution of 4-(N-tert-butoxycarbonylaminomethyl)aniline (756 mg, 3.4 mmol), 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.5 g, 4.08 mmol; prepared as described in Preparation 11) and HATU (1.55 g, 4.08 mmol) in DMF (6.8 mL), was added DIPEA (770 mL, 4.42 mmol). The reaction mixture was stirred at 50° C. overnight, and then the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was then dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (5-10% MeOH/DCM) to give a solid, which was dissolved in TFA/DCM (25%, 30 mL) and stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure and the crude residue was dissolved in DCM (30 mL) and washed with 1N NaOH (15 mL). The organic phase was separated, dried over MgSO4, filtered and the solvent was removed under reduced pressure to give 1.5 g of the title intermediate (94% yield over 2 steps).

Source