Benzaldehyde → (S)-1'-[2-Benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one Hydrochloride

Methanolic hydrogen chloride (4M, 2 mL) was added to a stirred, cooled (0° C.) solution of (S)-1'-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one (243 mg, 0.43 mmol) in methanol (2 mL) and the mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure, dichloromethane (5 mL), triethylamine (0.120 mL, 87 mg, 0.86 mmol), benzaldehyde (0.052 mL, 55 mg, 0.52 mmol) and magnesium sulfate (300 mg) were added. The mixture was stirred at room temperature for 4 h., filtered and the solvent was evaporated under reduced pressure. Methanol (5 mL) and sodium cyanoborohydride (54 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 1 h., aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. Methanol (25 mL) was added and the volume was reduced to 10 mL by distillation. The remaining solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1 increasing to 97:3:0.3). The residue was dissolved in methanol (5 mL), cooled to 0° C. and methanolic hydrogen chloride (1M, 0.23 mL) was added. The solvent was evaporated under reduced pressure and the residue was triturated with ether (5 mL). The solid was collected and dried in vacuo to give the title compound as a colorless solid (126 mg, 50%), mp. 173°-175° C. Found: C, 59.92; H, 5.14; N, 4.32. C30H30Cl2N2O4.HCl.0.5H2O requires: C, 60.16; H, 5.39; N, 4.68%. m/e (ES+) 553 (MH+).

1. additionwere added
2. stirringThe mixture was stirred at room temperature for 4 h.
3. filtrationfiltered
4. customthe solvent was evaporated under reduced pressure
5. stirringThe mixture was stirred at room temperature for 1 h.
6. extractionthe mixture was extracted with dichloromethane (3×20 mL)
7. dry with materialThe combined organic fractions were dried (MgSO4)
8. customthe solvent was evaporated under reduced pressure
9. additionMethanol (25 mL) was added
10. distillationthe volume was reduced to 10 mL by distillation
11. customThe remaining solvent was evaporated under reduced pressure
12. customthe residue was purified by flash column chromatography on silica gel
13. washeluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1 increasing to 97:3:0.3)
14. dissolutionThe residue was dissolved in methanol (5 mL)
15. temperaturecooled to 0° C.
16. additionmethanolic hydrogen chloride (1M, 0.23 mL) was added
17. customThe solvent was evaporated under reduced pressure
18. customthe residue was triturated with ether (5 mL)
19. customThe solid was collected
20. customdried in vacuo

ORD record

ord-09ec503db8e9477cb983c0043379a9d8

Source dataset

uspto-grants-1999_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05885999