反应 #1137

反应方程式

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

triphenylphosphine

potassium carbonate

DME

→

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

溶剂

water

反应条件

后处理

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

实验过程

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).

来源