Reaction #42139

Reaction equation

biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl) ethyl]piperidin-4-yl ester

4-aminobenzyl alcohol

HATU

DIPEA

DIPEA

DMSO

→

title intermediate

Yield 66.0%

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

Yield 66.0%

Solvents

DCM

DCM

Conditions

Workup

1. 1
   Washwashed first with a 1:3 mixture of 1N HCl/water (100 mL)
2. 2
   DryingThe organic layer was dried over MgSO4
3. 3
   Filtrationfiltered
4. 4
   Concentrationconcentrated
5. 5
   workup.DISSOLUTIONThe residue was dissolved in DCM (100 mL)
6. 6
   Temperaturethe solution was cooled to −5° C
7. 7
   workup.STIRRINGThe reaction mixture was stirred at 0° C. for 1 hour
8. 8
   Washthen washed with a saturated solution of sodium bicarbonate (100 mL) and brine (100 mL)
9. 9
   DryingThe organic layer was dried over MgSO4
10. 10
    Filtrationfiltered
11. 11
    Concentrationconcentrated

Procedure

A mixture of biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl) ethyl]piperidin-4-yl ester (1 g, 2.7 mmol; prepared as described in Preparation 14), 4-aminobenzyl alcohol (498 mg, 4.05 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.41 mL, 8.1 mmol) in DCM (14 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with 100 mL of DCM and washed first with a 1:3 mixture of 1N HCl/water (100 mL), then brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (100 mL) and the solution was cooled to −5° C. DIPEA (1.1 mL, 6.33 mmol) and DMSO (1.5 mL, 21.1 mmol) were added to the solution, followed by sulfur trioxide pyridine complex (1 g, 6.33 mmol). The reaction mixture was stirred at 0° C. for 1 hour then washed with a saturated solution of sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to give 0.84 g of the title intermediate (66% yield) as an oil.

Source