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To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 56.2 mL 4N HCl (dioxane). After stirring at ambient temperature for 2 hours, 200 mL of ether was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the hydrochloride salt of the product as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2g, 85% yield).
With sodium hydroxide; In water; ethyl acetate;
Step B: Preparation of (RV2-(2.5-difluorophenyl>pyrrolidine; To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 56.2 mL 4N HCl (dioxane). After stirring at ambient temperature for 2 hours, 200 mL of ether was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the hydrochloride salt of the product as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2g, 85% yield).
With sodium hydroxide; In water; ethyl acetate;
Step B: Preparation of (R)-2-(2.5-difluorophenyl)pyrrolidine.; To (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 4N HCl in dioxane (56.2 mL). After stirring at ambient temperature for 2 hours, ether (200 mL) was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the title compound hydrochloride salt as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2 g, 85% yield).[00418] The enantiomeric excess (% ee) of (R)-2-(2,5-difluorophenyl)pyrrolidine was determined as follows: To an ethanol solution of (R)-2-(2,5-difluorophenyl)pyrrolidine was added excess N-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (FDAA, Marfey's reagent). The mixture was heated to reflux for approximately two minutes. After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and analyzed by HPLC (YMC ODS-AQ 4.6 x 50 mm 3 mum 12thetaA column; mobile phase: 5-95% solvent B in A; solvent A: H2O/1% iPrOH/10 mM ammonium acetate, and solvent B: ACN/1% iPrOH /10 mM ammonium acetate; flow rate: 2 mL/min). The enantiomeric excess (ee%) was determined from the peak areas of the two diastereomeric derivatives formed. A 1 : 1 racemic standard was prepared according the same procedure described herein, replacing (R)-2-(2,5- difluorophenyl)pyrrolidine with (rac)-2-(2,5-difluorophenyl)pyrrolidine. The ee% of the title compound obtained as described above was determined to be > 93%.
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