With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.104706-47-0,(R)-3-Hydroxypyrrolidine hydrochloride,as a common compound, the synthetic route is as follows.
Boc2O (1.02 mL, 4.5 mmol) was added to a solution of (R)-3-hydroxylpyrrolidine hydrochloride (R)-2a¡¤HCl (0.50 g, 4.1 mmol) in THF-satd NaHCO3 (1:1, 20 mL), and the reaction mixture was stirred at rt for 1.5 h. EtOAc was added, and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate, which was used for the following reaction without further purification.The above-described tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate was dissolved in anhydrous DMF (20 mL), to which was added NaH (55% oil suspension, 0.71 g, 16.2 mmol) at 0 C. The ice-cold reaction mixture was stirred for 30 min, and Me2SO4 (0.77 mL, 8.1 mmol) was then added. The reaction mixture was stirred overnight at 50 C before being quenched with water. Hexane-EtOAc (1:1) was added, the layers were separated, and the aqueous layer was extracted three times with hexane-EtOAc (1:1). The combined organic layer was washed two times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 2:1) to afford 0.69 g of tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate [85% from (R)-2a¡¤HCl]. A colorless oil, -8.4 (c=0.52, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 1.44 (9H, s), 1.84-2.02 (2H, m), 3.31 (3H, s), 3.34-3.49 (4H, m), 3.91 (1H, brs). 13C NMR (125 MHz, CDCl3) delta: 28.5, 30.0, 31.1, 43.5, 43.9, 50.3, 51.1, 56.5, 79.09, 79.14, 79.9, 154.5, 154.6. IR (CHCl3): 1686, 1416 cm-1. HRMS Calcd for C10H19NNaO3 [(M+Na)+] m/z: 224.1257, found: 224.1248.Under a nitrogen atmosphere, 4 M HCl in EtOAc (1.2 mL) was added to tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate (50 mg, 0.25 mmol) at 0 C. The solution was stirred at rt for 30 min and concentrated in vacuo. The residue was dissolved in MeCN-water (10:1, 2.5 mL). Aqueous NH3 (30% w/w, 35 muL, 0.62 mmol) and 3 (162 mg, 0.62 mmol) were added to the solution at 0 C. The reaction mixture was stirred at rt for 30 min and concentrated in vacuo, and the residue was purified by flash column chromatography (CH2Cl2-MeOH, 15:1?10:1) to give 21 mg of (R)-1d (75%, 99% ee) and 7.1 mg of (R)-4-methoxy-1-pyrroline N-oxide (R)-4d (25%). The optical purity of (R)-1d was determined by Daicel CHIRALPAK AD-3 [hexane-iPrOH, 95:5, 2.0 mL/min; retention times 20.3 (R), 24.6 min (S)].(R)-1d. Pale yellow oil, +113 (c=0.85, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.17 (1H, dddd, J=3.5, 5.0, 9.0, 14.5 Hz), 2.48-2.57 (1H, m), 3.35 (3H, s), 3.87 (1H, dddd, J=1.0, 6.5, 9.0, 15.5 Hz), 4.10-4.19 (1H, m), 4.56-4.61 (1H, m), 7.02 (1H, q, J=1.5 Hz). 13C NMR (125 MHz, CDCl3) delta: 27.0, 56.5, 61.4, 80.0, 133.3. IR (CHCl3): 1584, 1269, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0534.(R)-4-Methoxy-1-pyrroline N-oxide [(R)-4d]. A pale yellow oil, -22.5 (c=0.66, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.75 (1H, d, J=19.5 Hz), 2.94-3.03 (1H, m), 3.33 (3H, s), 3.94 (1H, d, J=15.0 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, m), 6.84-6.87 (1H, m). 13C NMR (125 MHz, CDCl3) delta: 36.1, 56.5, 67.3, 74.3, 133.1. IR (CHCl3): 1595, 1275, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0533.
104706-47-0, 104706-47-0 (R)-3-Hydroxypyrrolidine hydrochloride 2759336, apyrrolidine compound, is more and more widely used in various fields.
Reference£º
Article; Nemoto, Hiroyuki; Tanimoto, Kouichi; Kanao, Yukiko; Omura, Sohei; Kita, Yasuyuki; Akai, Shuji; Tetrahedron; vol. 68; 36; (2012); p. 7295 – 7301;,
Pyrrolidine – Wikipedia
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