Reacción #338357

Ecuación de reacción

N-methylhydroxylamine hydrochloride

COMPOUND 249

Bis-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine

Et3N

phosgene

DIPEA

→

COMPOUND 325

Rendimiento 55.0%

4-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid hydroxy-methyl-amide

Rendimiento 55.0%

Disolventes

CH2Cl2

toluene

toluene

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawas then warmed up to room temperature
2. 2
   Otrosolvent was removed under reduced pressure (high vac.)
3. 3
   Otroto yield a yellow solid
4. 4
   workup.STIRRINGThe mixture was stirred at room temperature for 17 hours
5. 5
   OtroSolvent was removed under reduced pressure
6. 6
   workup.DISSOLUTIONthe residue was dissolved in CH2Cl2 (20 mL)
7. 7
   Extracciónextracted with saturated NaHCO3 (20 mL)
8. 8
   Secadodried over MgSO4
9. 9
   Filtraciónfiltered
10. 10
    Concentraciónconcentrated
11. 11
    OtroThe crude material was purified by column chromatography on silica gel (9:1:0.1 CH2Cl2:MeOH:NH4OH)

Procedimiento

To a 0° C. solution of COMPOUND 249 (236 mg, 0.760 mmol) in toluene (20 mL) and Et3N (0.45 mL, 3.42 mmol) was added phosgene solution in toluene (20 wt %, 0.519 mL, 1.14 mmol). The mixture was stirred at 0° C. for 2 hours, was then warmed up to room temperature and solvent was removed under reduced pressure (high vac.) to yield a yellow solid. Half of the solid (0.380 mmol) was dissolved in CH2Cl2 (10 mL) and DIPEA (0.5 mL) was added followed by N-methylhydroxylamine hydrochloride (48 mg, 0.57 mmol). The mixture was stirred at room temperature for 17 hours. Solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2 (20 mL), extracted with saturated NaHCO3 (20 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel (9:1:0.1 CH2Cl2:MeOH:NH4OH) to provide COMPOUND 325 as white solid (81 mg, 55%). 1H NMR (CDCl3) δ 1.60-1.73 (m, 3H), 1.92-2.00 (m, 2H), 2.09 (s, 6H), 2.65-2.76 (m, 3H), 2.95 (s, 3H), 3.83 (s, 4H), 4.12-4.18 (m, 2H), 7.09 (dd, 2H, J=4.2, 7.5 Hz), 7.37 (d, 2H, J=7.5 Hz), 8.34 (d, 2H, J=4.2 Hz); 13C NMR (CDCl3) δ 18.0, 27.1, 44.3, 45.5, 54.6, 57.4, 122.5, 133.4, 138.2, 145.9, 157.0, 165.8; ES-MS m/z 384 (M+H). Anal. Calcd. for C21H29N5O2.0.2H2O.0.5 CH2Cl2: C, 60.12; H, 7.13; N, 16.30. Found: C, 60.06; H, 7.09; N, 16.32.

Fuente