| 82% |
With thionyl chloride; at 0 - 20℃; for 2h;Inert atmosphere; |
Synthesis of methyl 5-oxopyrrolidine-2-carboxylate To a stirred solution of 5-oxopyrrolidine-2-carboxylic acid (10 g, 77.51 mmol) in MeOH (80 mL) under an argon atmosphere was added thionyl chloride (8.3 mL, 116.0 mmol) at 0 C. The reaction mixture was warmed to room temperature and stirred for 2 h. After consumption of starting material (monitored by TLC), the volatile components were concentrated in vacuo. The residue was diluted with a saturated sodium bicarbonate solution (200 mL) and extracted with 5% MeOH: CH2Cl2 (2*200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain methyl 5-oxopyrrolidine-2-carboxylate (9 g, 82%) as a colorless oil. TLC: 10% MeOH/CH2Cl2 (Rf: 0.4). |
| 59% |
With sulfuric acid; for 20h;Reflux; |
To the mixture of 5-oxopyrrolidine-2-carboxylic acid (5.165 g, 40 mmol) in methanol (150 mL) was added several drops ofconcentrated sulfuric acid. The resultant mixture was refluxed for 20 h. After cooled down, themixture was concentrated under reduced pressure and the residue was taken up by EtOAc (20mL), which was subsequently washed with saturated NaHCO3 (10 mL × 2), brine, and dried overNa2SO4. After removal of the solvent, the crude product was purified by flash column usingDCM/MeOH (50/1) to afford 3.360 g light yellow oil, in 59% yield. 1H NMR (400 MHz, CDCl3) 6.05 (brs, 1H, exchangeable), 4.26 (dd, J = 8.62 Hz, 5.02Hz, 1H), 3.78 (s, 3H), 2.48 (m, 1H),2.432.32 (m, 2H), 2.26 (m, 1H). IR (Diamond, cm-1) numax 2923.1, 1705.4, 1183.2. |
| 59% |
With sulfuric acid; for 20h;Reflux; |
Tothe mixture of 5-oxopyrrolidine-2-carboxylic acid (5.165 g, 40 mmol) inmethanol (150 mL) was added several drops of concentrated sulfuric acid. Theresultant mixture was refluxed for 20 h. After cooled down, the mixture wasconcentrated under reduced pressure and the residue was taken up by EtOAc (20mL), which was subsequently washed with saturated NaHCO3 (10 mL ×2), brine, and dried over Na2SO4. After removal of thesolvent, the crude product was purified by flash column using DCM/MeOH (50/1)to afford 3.360 g light yellow oil, in 59% yield. 1H NMR (400 MHz,CDCl3) d 6.05(brs, 1H, exchangeable), 4.26 (dd, J = 8.62 Hz, 5.02Hz, 1H),3.78 (s, 3H), 2.48 (m, 1H), 2.43-2.32 (m, 2H), 2.26 (m, 1H).IR (Diamond, cm-1) numax 2923.1, 1705.4, 1183.2 |
| 58% |
With thionyl chloride; at 0 - 20℃; for 16h; |
To a solution of 5- oxopyrrolidine-2-carboxylic acid (9.00 g, 69.7 mmol) in MeOH (20 mL) was added SOCl2 (6.60 mL, 90.6 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with H20 (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with H20 (20 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated in vacuo to afford methyl 5- oxopyrrolidine-2-carboxylate (5.60 g, 58%) as a colorless liquid. This compound was used as such for the next reaction without further purification. MS (ESI) m/e [M+]+/RT (min)/%: (0360) 144.00/1.33/68.6% . 1H NMR (400 MHz, DMSO- 6) delta 2.04-2.18 (m, 2H), 3.56-3.62 (m, 2H), 3.70 (s, 3H), 4.16-4.22 (m, 1H), 7.97 (s, 1H). |
| 39% |
With thionyl chloride; at 0 - 70℃; for 16h; |
To a stirred solution of 5-oxopyrrolidine-2-carboxylic acid (10 g, 77.4 mmol) in MeOH (100 mL) thionyl chloride (6.7 mL, 92.9 mmol) was added at 0 C and the reaction mixture was stirred at 70 C for 16 h. The progress of the reaction was monitored by TLC. The excess of MeOH was evaporated, the residue was diluted with EtOAc (2x25 mL), the combined organic layer was stirred over K2C03 (3 g), washed with water (20 mL) and brine (20 mL) and separated the organic layer, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (4.3 g, 39% yield) as brown liquid. (0578) 1H NMR (500 MHz, CDCI3) delta: 6.12 (s, 1 H), 4.27 (q, J=5.44 Hz, 1 H), 3.79 (s, 3H), 2.51 -2.41 (m, 1 H), 2.43-2.37 (m, 2H), 2.34-2.24 (m, 1 H). |
|
With sulfuric acid; In toluene; for 40h;Heating / reflux; |
Example 1A 5-Oxo-pyrrolidine-2-carboxylic Acid Methyl Ester To a solution of DL-pyroglutamic acid (50 g, 0.387 mol) in 157 mL CH3OH (3.87 mol) and 100 mL toluene was added concentrated H2SO4 (2.5 mL). This mixture was warmed to reflux and allowed to stir for 16 h. Since starting material remained, another 4 mL concentrated H2SO4 was added and the mixture stirred at reflux for an additional 24 h then was cooled to ambient temperature and 20% aqueous NaOH was added to bring the solution to pH ~6. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2, filtered through Celite diatomaceous earth, concentrated and purified via Kugelrohr distillation. The resulting material was carried on directly to the next reaction. |
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