| 89.0% |
With trichlorophosphate; In pyridine; ice-water; hexane; |
(1) 5.1 g of (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (Liebich's Annalen der Chemie 529 (1937), page 1) are dissolved in 20 ml of pyridine, and 50 ml of tert.-butanol are added thereto. The solution is cooled to a temperature below -5 C., and 3.5 g of phosphorous oxychloride are added dropwise thereto. The mixture is stirred at the same temperature for about 30 minutes and then at room temperature for 3 hours. The reaction mixture is poured into 200 ml of ice-water, and extracted with ethyl acetate. The extract is washed with 1% hydrochloric acid, an aqueous sodium bicarbonate solution and water, successively. Then, the extract is dried and evaporated to remove solvent. The residue obtained is crystallized with a mixture of ether and n-hexane. 5.5 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.0% M.p. 138-139 C. IR numaxnujol (cm-1): 3270, 1790, 1760, 1740 |
| 62.2% |
With pyridine; In chloroform; trichlorophosphate; at 0 - 20℃; for 4.5h; |
Phosphorus oxychloride (3.3 g, 2.0 mL, 22 mmol) was added to a solution of (S) -3 - ((benzyloxy) carbonyl) -2- oxoimidazolidine-4-carboxylic acid (3.91 g, 14.8 mmol ),Pyridine (9 mL), chloroform (20 mL) and t-butanol (12 mL).After stirring at 0 C for 30 minutes, the mixture was stirred at room temperature for 4 hours.The reaction was slowly added to a solution of sodium acetate (30 g) in ice water (200 mL) to quench the reaction. The resulting mixture was extracted with chloroform (100 mL) and the combined organic layers were washed sequentially with 0.1 M dilute hydrochloric acid (50 mL), water (50 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent .The resulting residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 2/3) to give the title compound as a white solid (2.95 g, 62.2%). |
| 43% |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 17.0h; |
(S)-(-)-1-Z-2-oxo-5-imidazolidinecarboxylic acid (2.0 g, 7.569 mmol, 1 eq.), DMAP (92.5 mg, 0.757 mmol, 0.1 eq.) and tert-butanol (2.17 mL, 22.71 mmol, 3 eq.) were dissolved in CH2CI2 (38 mL). The reaction was cooled to 0 C and EDC (1.74 g, 9.083 mmol, 1.2 eq.) was added. The reaction was left at 0 C for 1 h and stirred at RT for 16 hrs. The solvent was evaporated and the product was purified by normal phase column chromatography using 15 % to 70 % ethyl acetate in hexanes as the eluent to give (5S)-1-benzyl 5-tert-butyl 3-(cyclohex-2-en-1-yl)-2-oxoimidazolidine-1,5-dicarboxylate as a white solid (1.05 g, 43%). 1H NMR (400 MHz, CDC13) delta 1.38 (9H, s), 3.38 (1H, dd, J=4, 7Hz), 3.73 (1H, t, J=10Hz), 4.63 (1H, dd, J=4, 10 Hz), 5.20-5.33 (4H, m), 6.25 (1H, s), 7.30-7.40 (5H, m), (LC/MS) m/z observed 320.82, expected 321.15 [M+H]. |
| 43% |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 17.0h; |
(<S)-(-)-l-Z-2-Oxo-5-imidazolidinecarboxylic acid (2.0 g, 7.569 mmol, 1 eq.), DMAP (92.5 mg, 0.757 mmol, 0.1 eq.) and ferf-butanol (2.17 mL, 22.71 mmol, 3 eq.) were dissolved in CH2CI2 (38 mL). The reaction was cooled to 0 C and EDC (1.74 g, 9.083 mmol, 1.2 eq.) was added. The reaction was left at 0 C for 1 h and stirred at RT for 16 hrs. The solvent was evaporated and the product was purified by normal phase column chromatography using 15 % to 70 % ethyl acetate in hexanes as the eluent to give (<S)-1- benzyl 5-ferf-butyl 2-oxoimidazolidine-l,5-dicarboxylic acid as a white solid (1.05 g, 43%). NMR (400 MHz, CDC13) delta 1.38 (9H, s), 3.38 (1H, dd, J=4, 7Hz), 3.73 (1H, t, J=10Hz), 4.63 (1H, dd, J=4, 10 Hz), 5.20-5.33 (4H, m), 6.25 (1H, s), 7.30-7.40 (5H, m), (LC/MS) m/z observed 320.82, expected 321.15 [M+H]. |
|
With pyridine; trichlorophosphate; In chloroform; at -10 - 20℃; for 4.5h; |
The 3-methyl-1-(6-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt used in the method described above was prepared as follows: Step (i) Phosphorus oxychloride (2.2 ml, 24 mmol) was added dropwise to a stirred solution of (4S)-2-oxo-3-[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid (5.28 g, 20 mmol) in pyridine (10 ml) , tert-butanol (15 ml) and chloroform (25 ml) at -10 0C. The mixture was stirred at -5 to 00C for 30 minutes and then at room temperature for 4 hours. The solution was added dropwise to stirred ice water (200 ml) containing sodium acetate (~ 40 g). The mixture was diluted with chloroform (100 ml) and the mixture was stirred for 30 minutes. The organic layer was separated, washed with cold 0.1 M hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4) and evaporated. The residue was dried to give 5-(1 ,1-dimethylethyl) i-(phenylmethyl) 2-oxo-1 ,5- imidazolidinedicarboxylate (5.65 g, 88%) as a colourless solid. LC/MS [M+H]+ = 321. [For a method similar to this step (i), see: K. Hayashi et al., J. Med. Chem., 1989, 32(2), 289-297; e.g. see Scheme 1 and compounds (5) and (6a) on p.289 therein and synthesis of compound (6a) in p.293 experimental section therein, incorporated herein by reference.] |
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