Uses
(2R)-N-Boc-4-oxo-proline was used as a reactant in the preparation of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides which are potent factor Xa inhibitors with increased human half life. Also used in the synthesis of azacyclic FTY720 analogues which show potential for use in strategy to kill cancer cells as they restrict access to extracellular nutrients.
Synthesis
Step 1: Preparation of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a). At 0 °C, (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (51 g, 221 mmol) was dissolved in dichloromethane (2023 mL), trichloroisocyanuric acid (51.3 g, 221 mmol) and TEMPO (1.723 g, 11.03 mmol) were added. Stirring was maintained at 0°C for 30 min, then slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and stirring was continued for 30 min. Subsequently, dichloromethane was removed by distillation under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and filtered through a diatomaceous earth plug. The filtrate was acidified with 1 M HCl (8 mL) and the organic layer was separated. The ethyl acetate layer was washed sequentially with water (4 x 200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the white solid product (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a) (38 g, 166 mmol, 75% yield). The product was confirmed by 1H NMR (300 MHz, DMSO-d6) and mass spectrometry (ES-).
References
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 6, p. 2501 - 2511
[2] Patent: WO2017/59178, 2017, A1. Location in patent: Page/Page column 105
[3] Patent: WO2004/87646, 2004, A2. Location in patent: Page/Page column 63-64
[4] Patent: WO2017/117239, 2017, A1. Location in patent: Page/Page column 53; 54
