99.6% |
With 1-methyl-pyrrolidin-2-one; hydrogenchloride; In water; |
Example 2-1 (6-(3R,4R)-3-hydroxy-4-methoxypyrrolidine)-2-benzylpyridine In the atmosphere of nitrogen, to a 2L four necked flask were added (3R,4R)-<strong>[153199-54-3]3-hydroxy-4-methoxypyridine</strong> (106 g, 0.91 mol), 6-bromo-2-benzylpyridine (150 g, 0.605 mol) [see Tetrahedron Letters, 21, pp. 845-848 (1980)], 1,8-diazabicyclo[5.4.0]-undeca-5-ene (92 g, 0.605 mol) and N-methylpyrrolidone (150 mL). Then, under stirring, the solution was heated in an oil bath at 110 C. for 11 hours. (3R,4R)-<strong>[153199-54-3]3-hydroxy-4-methoxypyridine</strong> (10.6g, 0.09 mol) was added thereto. Under stirring, the solution was heated in an oil bath of 110 C. for 1 hour. The solution was left at room temperature, and then thereto were added 450 mL of t-butyl methyl ether and 450 mL of water. While the temperature of the inside was kept at 20 C. or less by an ice bath, 2 N hydrochloric acid was dropwise added to the solution until the pH of the solution was 6. The solution was transferred to a 2 L separatory funnel. The upper layer was separated, and the remaining aqueous layer was again subjected to extraction with 300 mL of t-butyl methyl ether. The t-butyl methyl ether layers were combined, followed by washing with 300 mL of water and 300 mL of saturated salt water. The upper layer was dried over anhydrous magnesium sulfate, and washed with 100 mL of t-butyl methyl ether. The filtrate was concentrated under reduced pressure at 40 C. to give 171 g (crude yield: 99.6%) of the captioned compound as a black brown oily material. 1H-NMR(400 MHz, CDCl3): 3.42 (3H, s), 3.49 (1H, dd, J=3, 12 Hz), 3.52 (1H, dd, J=3, 12 Hz), 3.71 (1H, dd, J=5, 12 Hz), 3.75 (1H, dd, J=5, 12 Hz), 3.85-3.88 (1H, m), 3.97 (2H, s), 4.38-4.40 (1H, m), 6.16(1H, d, J=8 Hz), 6.35(1H, d, J=8 Hz), 7.17-7.34 (6H, m) |