Methyl iodide → 1-Ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone

To a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. was added, drop-wise, a solution of 1-ethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (1.34 g, 3.48 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was stirred for 1 hr at −78° C. Iodomethane (0.239 ml, 3.82 mmol) was then added and after stirring for a further 1 hr at −78° C. the mixture was allowed to warm to room temperature over 3 hrs. The mixture was then re-cooled to −78° C. and treated, drop-wise, with a further aliquot of a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol). After stirring for an additional 1 hr at −78° C. the mixture was again treated with iodomethane (0.239 ml, 3.82 mmol) and then the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (2×). The combined organic extracts were then washed with water (3×) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated to a crude oily solid (1.7 g). The crude solid was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give pure product fractions (i.e. 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.468 g)) as well as pure monoalkylated material (i.e. 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.524 g)) and a mixture of these two (0.240 g). The desired product was set aside while the 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone and the mixed material were combined and dissolved in tetrahydrofuran (20 ml). This solution was then added drop wise to a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. and stirring at this temperature was continued for 1 hr. Iodomethane (0.239 ml, 3.82 mmol) was then added to the mixture and the mixture was allowed to warm to room temperature over 4 hrs. Workup as described above gave an additional batch of 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.846 g) as an oil which was combined with the material set aside earlier (total mass=1.08 g) and used in the next step without further purification.

ORD record

ord-7004fc6bc7124f1bbeda456e3d024741

Source dataset

uspto-grants-2010_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07718693B2