4-Piperidinecarboxamide → Biphenyl-2-ylcarbamic Acid 1-(2-{[4-(4-Carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl Ester

Temperatur

5 °C

To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10° C. with an ice bath and a solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×250 mL). The aqueous phase was then cooled to 0-5° C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3×300 mL) and the combined organic layers were washed with water (100 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M+H+] calc'd for C35H43N5O4 598.3. found 598.6. Rf=2.32 min (10-70 ACN:H2O, reverse phase HPLC).

1. temperaturecooled to 0-10° C
2. stirringthis mixture was stirred at room temperature for 16 hours
3. concentrationThe reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL
4. stirringThe resulting mixture was stirred at room temperature for 1 hour
5. extractionextracted with DCM (3×250 mL)
6. temperatureThe aqueous phase was then cooled to 0-5° C. with an ice bath
7. addition50% aqueous NaOH solution was added
8. extractionThis mixture was then extracted with isopropyl acetate (3×300 mL)
9. washthe combined organic layers were washed with water (100 mL), brine (2×50 mL)
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated

ORD-Eintrag

ord-1a84a224fc264e43a2bbc5c90887c6bb

Quelldatensatz

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09249099B2