反应详情

温度

-78 °C

According to WO 2008/053319, to a solution of (−)-sparteine (2.7 g, 11.7 mmol) and pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 11.7 mmol) in dry methyl tert-butyl ether was added at −78° C. 1.4 M sec-butyllithium in cyclohexane (8.3 ml, 11.7 mmol) over 30 min and the mixture was stirred at −78° C. for 3 h. 0.5 M zinc chloride solution in tetrahydrofuran (14 ml, 7 mmol) was added at −78° C. and the mixture was stirred for 30 min at −78° C. and 30 min at 25° C. This mixture was added via a syringe to a solution of 2-bromopyrazine (1.48 g, 9.34 mmol), palladium(II) acetate (105 mg, 0.467 mmol) and tetrafluoroboric acid tri-tert-butylphosphine adduct (169 mg, 0.584 mmol) at −78° C. The mixture was stirred and allowed to slowly warm to 25° C. overnight. The solid was filtered off, to the solution was added aqueous sodium hydrogencarbonate, and the mixture was extracted 3 times with dichloromethane, solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 750 mg of crude product which was dissolved in dichloromethane (5 ml) and treated with 4 N hydrogen chloride in dioxane (0.8 ml, 3.2 mmol) for 2 days, and after addition of water was lyophilized to give 200 mg (17%) of crude (R)-2-pyrrolidin-2-yl-pyrazine hydrochloride which was used without purification in the next step. LC/MS (method 7): Rt=0.14 min; m/z=150.1 (M+H+).

1. additionwas added at −78° C
2. stirringthe mixture was stirred for 30 min at −78° C. and 30 min at 25° C
3. stirringThe mixture was stirred
4. temperatureto slowly warm to 25° C. overnight
5. filtrationThe solid was filtered off, to the solution
6. additionwas added aqueous sodium hydrogencarbonate
7. extractionthe mixture was extracted 3 times with dichloromethane, solvents
8. customwere evaporated
9. customthe residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)
10. customto give 750 mg of crude product which