Methyl iodide → HCID 10133302, compound

A suspension of compound (2S)-(3-amino-2-fluoropropyl)phosphinic acid (1.2 g, 8.5 mmol) in HMDS (8.96 mL, 42.4 mmol) was heated to reflux for 15 h. The reaction was cooled to room temperature, treated with diglyme (9.6 mL) and heated to reflux for 7 h. After the mixture was cooled to room temperature, Hünig's base (1.47 mL, 8.4 mmol) was added followed by dropwise addition of methyl iodide (1.58 mL, 25.4 mmol). The reaction was stirred overnight then it was diluted with methylene chloride and extracted with 2 N HCl solution. The aqueous layer was washed with methylene chloride and diethyl ether and then evaporated under reduced pressure. The crude product was passed through a Dowex 50WX8-200 mesh H+ form column eluting with 1:1 methanol/water until no further material was detected by TLC analysis. The product was then eluted with 1:3 concentrated ammonium hydroxide solution/methanol. Further purification by column chromatography on silica gel eluting with methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1) afforded (2S)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid as a white solid (504 mg, 38%). 1H NMR (300 MHz, D2O) δ5.20 (m, 0.5H), 5.03 (m, 0.5H), 3.20-3.42 (m, 2H), 1.80-2.22 (m, 2H), 1.30 (d, J=14.0 Hz, 3H).

1. temperaturewas heated
2. temperatureto reflux for 15 h
3. temperatureheated
4. temperatureto reflux for 7 h
5. temperatureAfter the mixture was cooled to room temperature
6. extractionextracted with 2 N HCl solution
7. washThe aqueous layer was washed with methylene chloride and diethyl ether
8. customevaporated under reduced pressure
9. washeluting with 1:1 methanol/water until no further material
10. washThe product was then eluted with 1:3 concentrated ammonium hydroxide solution/methanol
11. customFurther purification by column chromatography on silica gel eluting with methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1)

ORD record

ord-eb872f035b8547c9a337e42e819dacb1

Source dataset

uspto-grants-2003_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06596711B1