BOC-TRANS-4-FLUORO-L-PROLINE METHYL ESTER

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

Procedure: (2S,4R)-4-Fluoro-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide 79A was prepared from (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate as described for 65A and 65B. LC/MS [M+H]+: 228; Ret time (Method C): 0.57 min. 0.57 min.

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

Procedure: To a solution of aminopyrazine (3.85 g, 40.5 mmol) in THF (120 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 19 mL, 38 mmol) dropwise at 0° C. The resulting slurry was stirred at room temperature for 30 min. A solution of commercially available (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (3.2 g, 12.9 mmol) in THF (10 mL) was added to the slurry. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). After concentration in vacuo, ethyl acetate (120 mL) and 1N HCl (60 mL) were added to the residue. The organic layers were washed with 1N HCl, water, brine, and dried over Na2SO4, and filtered. Concentration gave (2S,4R)-tert-butyl 4-fluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 65A (4.1 g, 100%) as a colorless foam. LC/MS [M+H]+: 311; Ret time (Method F): 1.46 min. The reaction mixture was stirred at room temperature for 4 h quenched with methanol (3 mL) After concentration in vacuo, ethyl acetate (120 mL) and 1N HCl (60 mL) were added to the residue The organic layers were washed with 1N HCl, water, brine dried over Na2SO4 filtered Concentration