Malonic Acid → HCID 10493294, compound

A mixture of 3-pyridinecarboxaldehyde (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 (E. Profft, J. Prakt. Chem. 1965, 30, 18). 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 racemic 3-phenylacetamido-3-(3-pyridyl)propionic acid. A solution of this compound (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. 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 the sodium salt. This material was treated with MeOH (500 mL), 2,2-dimethoxypropane (44 mL), and HCI (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 AA4 (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 (E. Profft, J. Prakt. Chem. 1965, 30, 18)
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)

ORD record

ord-03d9afa3f93b417da5cfe515b778eb5a

Source dataset

uspto-grants-2001_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06303625B1