反应详情

温度

85 °C

A solution of acetamidine hydrochloride (12.8 g, 135 mmol) and sodium ethoxide (59 mL, 157.5 mmol) in anhydrous ethanol (400 mL) was stirred under nitrogen for 15 min, and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one from Step B (17.2 g, 45 mmol) was added. The resulting mixture was heated at 85° C. for 3.5 h, quenched with a solution of 5% aqueous citric acid (50 mL), and evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution. There was some insoluble solid material between the aqueous and the organic layers, which was filtered thorough a Celite pad and washed with ethyl acetate. The combined aqueous layers were extracted twice with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by chromatography on a Biotage Horizon® system (silica gel, 10-75% ethyl acetate/dichloromethane gradient) to yield the N-trityl protected derivative of the desired product. A portion of this trityl protected product (1.9 g, 5.0 mmol) was dissolved in 4N methanolic hydrogen chloride (20 mL) and stirred at room temperature for 2.5 h. The solution was evaporated and the residue was purified by chromatography on a Biotage Horizon® system (silica, 4.5-14% gradient of 10% concentrated aqueous ammonium hydroxide in methanol/dichloromethane) to yield the desired product. LC-MS=136.0 (M+1).

1. customquenched with a solution of 5% aqueous citric acid (50 mL)
2. customevaporated to dryness
3. dissolutionThe residue was dissolved in ethyl acetate (500 mL)
4. washwashed with saturated aqueous sodium bicarbonate solution
5. filtrationwas filtered thorough a Celite pad
6. washwashed with ethyl acetate
7. extractionThe combined aqueous layers were extracted twice with ethyl acetate
8. washwashed with saturated aqueous sodium bicarbonate solution and brine
9. dry with materialdried over anhydrous sodium sulfate
10. concentrationconcentrated
11. customThe residue obtained
12. customwas purified by chromatography on a Biotage Horizon® system (silica gel, 10-75% ethyl acetate/dichloromethane gradient)