Formaldehyde → (1-Methylpiperidin-4-yl)methyl 4-(4-methylphenyl)-piperazine-1-carboxylate

Temperature

95 °C

(1-piperidin-4-yl)methyl 4-(4-methylphenyl)piperazine-1-carboxylate (Example 3; 9.75 g, 30.7 mmol) was dissolved in formic acid (3 mL), 35% aqueous formaldehyde solution (3 mL) and water (20 mL). The reaction mixture was heated at 95° C. for 45 minutes, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto 1M aq Na2CO3 solution (400 mL) and extracted with EtOAc (4×150 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from heptane and then purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo. The residue was recrystallised from heptane to give (1-methylpiperidin-4-yl)methyl 4-(4-methylphenyl)-piperazine-1-carboxylate (4.38 g, 43.0%) as a white solid.

1. temperaturecooled to room temperature
2. customThe reaction mixture was quenched
3. additionby slowly pouring it onto 1M aq Na2CO3 solution (400 mL)
4. extractionextracted with EtOAc (4×150 mL)
5. washThe combined organic layers were washed with brine (75 mL)
6. dry with materialdried (MgSO4)
7. concentrationconcentrated in vacuo
8. customThe residue was recrystallised from heptane
9. custompurified by reverse phase column chromatography (gradient
10. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-30%)
11. dissolutionThe resulting residue was dissolved in DCM (70 mL)
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue was recrystallised from heptane

ORD record

ord-babba1304fc948e1b2aba3bed884d7fa

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093248B2