Diethyl methylphosphonate → Diethyl(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate

Temperature

-78 °C

A solution of diethyl methylphosphonate (1.27 g, 8.36 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. in a dry ice-acetone bath under nitrogen. Then n-BuLi (9.77 mmol, 3.9 mL, 2.5M in hexane) was added dropwise over about 5 min. The reaction mixture was stirred for about 3 h, keeping the temperature below about −70° C. Then a solution of methyl 4-(cyclopropanesulfonamido)bicyclo[2.2.2]octane-1-carboxylate (800 mg, 2.79 mmol) in THF (10 mL) was added, keeping the temperature at about −78° C. The solution was stirred for about 15 h, allowing the temperature to rise slowly to rt. To the reaction mixture was added saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined and washed with brine, dried over anhydrous Na2SO4 and concd to provide diethyl(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)methylphosphonate (1.30 g, 100% yield). The crude product was used in next step without further purification. LC/MS (Table 1, Method p) Rt=1.62 min; MS m/z: 408 (M+H)+.

1. customthe temperature below about −70° C
2. customat about −78° C
3. stirringThe solution was stirred for about 15 h
4. customto rise slowly to rt
5. extractionextracted with EtOAc (3×30 mL)
6. washwashed with brine
7. dry with materialdried over anhydrous Na2SO4 and concd

ORD record

ord-41e098557fde4ec9bb540bf837ae7322

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426411B2