Hydrochloric Acid → HCID 69848410, compound

Phenylacetamide intermediate AG3 was prepared using standard methods as shown in Scheme AG (E. Profft, J. Prakt. Chem. 1965, 30, 18). A mixture of AG1 (0.47 mol), EtOH (100 mL), NH4OAc (0.47 mol), and malonic acid (0.70 mol) was heated at reflux for 6 h, cooled, and filtered. The white solid was washed with EtOH and MeOH and dried. This solid was dissolved in 2:1 acetone/water (360 mL), treated with triethylamine (0.72 mol) and phenylacetyl chloride (0.36 mol), and stirred for 22 h. The mixture was evaporated and the residue dissolved in water (500 mL) and adjusted to pH 12 (1 N NaOH). The aqueous layer was adjusted to pH 2 (conc. HCl), extracted with Et2O, and evaporated to a white foam. The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3. A solution of compound AG3 (0.22 mol) in water (600 mL) at RT was adjusted to pH 7.5 using KOH (3.0 N) and treated with penicillin amidase (91520 units, Sigma). This mixture was stirred for 47 h, acidified to pH 1 with HCl (conc), and the resultant ppt filtered through Celite. The filtrate was extracted with Et2O (3×300 mL), concentrated in vacuo, and treated with MeOH/conc. NH4OH (9:1). This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4) to give (S)-3-phenylacetamido-3-(3-pyridyl)propionic acid ammonium salt (19.5 g, 58%). This product was treated with HCl (6.0 N, 292 mL), heated at reflux for 5 h, cooled to RT, and extracted with Et2O (3×200 mL). The aqueous layer was adjusted to pH 12, concentrated in vacuo, and the resultant solid triturated with MeOH (2×300 mL). This solution was evaporated to give ca. 14 g sodium salt. This material was treated with MeOH (500 mL), 2,2-dimethoxypropane (44 mL), and HCl (4 N in dioxane, 84 mL), and stirred for 90 h at RT. This mixture was filtered and the filtrate concentrated in vacuo. The resultant off-white solid was triturated with Et2O (2×150 mL) and dried to give compound AG5 (16.7 g, 96% ee) as a white, amorphous solid.

1. temperaturewas heated
2. temperatureat reflux for 6 h
3. temperaturecooled
4. filtrationfiltered
5. washThe white solid was washed with EtOH and MeOH
6. customdried
7. dissolutionThis solid was dissolved in 2:1 acetone/water (360 mL)
8. customThe mixture was evaporated
9. dissolutionthe residue dissolved in water (500 mL)
10. extractionextracted with Et2O
11. customevaporated to a white foam
12. customThe foam was purified by silica gel chromatography (10% MeOH/DCM)
13. customto give AG3
14. customat RT
15. stirringThis mixture was stirred for 47 h
16. filtrationthe resultant ppt filtered through Celite
17. extractionThe filtrate was extracted with Et2O (3×300 mL)
18. concentrationconcentrated in vacuo
19. additiontreated with MeOH/conc
20. customThis product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:18:4)

ORD record

ord-ea4eae7d61984f9ea2ad01de21414ddf

Source dataset

uspto-grants-2000_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06069254