General procedure for the synthesis of (S)-4,4-difluoropyrrolidine-2-carboxylic acid from N-Boc-4,4-difluoro-L-proline:
1. (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (500 mg, 1.99 mmol) was dissolved in methanol (30 mL).
2. To the above solution was added a dioxane solution (3 mL) of 4N HCl.
3. The reaction mixture was stirred at room temperature for 6 hours.
4. Upon completion of the reaction, the reaction solution was concentrated to give an oily product (480 mg, 100% yield), which could be used in the next step without further purification. 5. The structure of the product was determined by 1H NCl and the reaction was carried out in aqueous solution.
5. The structure of the product was confirmed by 1H NMR (CD3OD, 400 MHz): δ 4.76 (1H, t, J = 8.5 Hz), 3.79-3.87 (2H, m), 2.91-3.03 (1H, m), 2.73-2.82 (1H, m).
