[(2R)-4,4-dimethylpyrrolidin-2-yl]methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of triethylamine (4.94 mL, 35.4 mmol) and (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride (1.0 M in DCM, 21.27 mL, 21.27 mmol) over 15 seconds. The reaction was maintained at this temperature for ˜3 h, allowed to warm to room temperature and stirred overnight (16 h). The mixture washed with aqueous 1 N HCl (30 mL×2), brine (40 mL), dried over MgSO4, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (708 mg, 3.70 mmol, 21% yield) as a white crystalline solid. MS (ESI) 192.1 [M+H]+. The reaction was maintained at this temperature for ˜3 h The mixture washed with aqueous 1 N HCl (30 mL×2), brine (40 mL) dried over MgSO4 filtered concentrated affording crude product as a brown-orange oil that crystallized The crude material was absorbed onto a plug of silica gel purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to US patent: 20070032433A1. To a solution of (R)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.30 mmol) in THF (50.8 mL) cooled to 0° C., lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added. The mixture was stirred at room temperature overnight (16 h). Additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the solution was refluxed for 6 h. The reaction mixture was cooled and additional lithium aluminum hydride (2.0 M solution in THF, 12.18 mL, 24.36 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to 0° C. in an ice bath prior to addition of water (3.67 mL) followed by 15% aqueous NaOH (3.67 mL) and water (10.9 mL). It was then stir vigorously at room temperature for 1 h and filtered on a medium porosity sintered glass frit with cotton and celite washing with EtOAc. The solution was then concentrated affording crude (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.73 mmol, 87% yield) as yellow viscous oil. MS (ESI) 130.1 [M+H]+. Prepared the solution was refluxed for 6 h The reaction mixture was cooled the mixture was refluxed overnight The reaction mixture was cooled to 0° C. in an ice bath It was then stir vigorously at room temperature for 1 h filtered on a medium porosity sintered glass frit with cotton and celite washing with EtOAc The solution was then concentrated