反応 #1137

反応方程式

5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine

triphenylphosphine

potassium carbonate

DME

→

5-propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine

溶媒

water

反応条件

後処理

1. 1
   その他The vessel was evacuated
2. 2
   workup.ADDITIONpropyne gas was introduced to a pressure of 20 p.s.i
3. 3
   ろ過Analysis by GC at this stage indicated about 40% completion and the cooled mixture was filtered through celite
4. 4
   濃縮the filtrate concentrated in vacuo
5. 5
   抽出extracted with toluene (50 mL)
6. 6
   抽出extracted with ethyl acetate (2×100 mL)
7. 7
   洗浄The combined ethyl acetate extracts were washed with water (50 mL)
8. 8
   乾燥dried (MgSO4)
9. 9
   濃縮concentrated
10. 10
    その他to afford an oil
11. 11
    その他The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:1) as eluant

実験手順

A Parr hydrogenation vessel was charged with 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (1 g, 4.15 mmol), 10% palladium on charcoal (106 mg, 0.1 mmol), copper(I)iodide (38 mg, 0.2 mmol), triphenylphosphine (104 mg, 0.4 mmol) and potassium carbonate (1.38 g, 10 mmol), DME (10 mL) and water (10 mL). The vessel was evacuated and propyne gas was introduced to a pressure of 20 p.s.i. The mixture was agitated and heated at 90° C. for 6 days, readmitting propyne gas as necessary. Analysis by GC at this stage indicated about 40% completion and the cooled mixture was filtered through celite and the filtrate concentrated in vacuo. The mixture was then acidified with 1M HCl (50 mL) and extracted with toluene (50 mL). The aqueous layer was made basic with solid potassium carbonate and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (50 mL), dried (MgSO4) and concentrated to afford an oil. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:1) as eluant to afford 5-propynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (250 mg, 30%). A portion (225 mg) of this material was converted to the title compound by the addition of one equivalent of fumaric acid to a methanol (10 mL) solution of the free amine at 25° C. After 30 minutes the solvent was removed in vacuo and the residue pumped under high vacuum. Trituration with diethyl ether followed by recrystallization from ethyl acetate afforded 5-[1-(1-propynyl)]-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate, 180 mg, 50%. M.p. 188°-189° C. (EtOAc); 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 6.60 (s, 2H), 3.34 (t, J=9 Hz, 1H), 3.25 (app. t, J=9 Hz, 1H), 2.41 (dd, J=9, 9 Hz, 1H), 2.22 (m, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 1.85 (m, 2H), 1.69 (m, 1H).

出典