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α-(3,4-Dichlorophenyl)-1-pyrrolidinepropanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; paraformaldehyde; In ethanol;
Preparation 11 α-(3,4-Dichlorophenyl)-1-pyrrolidinepropanenitrile To 100 mL of ethanol is added (18.6 g (0.1 mol) 3,4-dichlorobenzeneacetonitrile, 12.6 g (0.12 mol) of <strong>[25150-61-2]pyrrolidine hydrochloride</strong>, 6.0 g (0.2 mol) of paraformaldehyde and 1 mL of concentrated hydrochloric acid. Stir the mixture at reflux. Monitor the progress of the reaction by thin-layer chromatography. Upon completion add 300 mL of 1N HCl and extract with 200 mL of Et2 O. Add 4N NaOH to the aqueous solution until basic and extract the aqueous solution with two 100 mL portions of CH2 Cl2. Dry the organic phase over anhydrous Na2 SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
2-(3,4-dichlorophenyl)acetonitrile (3.50 g, 18.8 mmol) was taken up in THF (30 mL) and diethyl ether (30 mL), and cooled to -78 °C in an acetone-dry ice bath. BuLi (8.1 mL, 20 mmol, 1.6 M in hexane) was added drop-wise, and the temperature was maintained below -60 °C. Once the last drop had been added, the reaction was allowed to stir for 15 minutes. This solution became orange clear. 6- methoxypicolinaldehyde (2.3 mL, 19 mmol) dissolved in THF (20 mL) was added slowly drop-wise, and the temperature was maintained below -60 °C. Solution was dark brown / black clear at this point and was allowed to stir for 1.5 hours at -75 °C. The reaction was quenched with acetic acid (1.6 mL, 28 mmol) dissolved in 5 mL of diethyl ether, added drop-wise while the reaction was cooled in the dry ice acetone bath. The temperature was maintained below -60 °C. LCMS revealed mostly one peak with the desired mass. The reaction was worked up by adding 100 mL of water, and layers were separated. The aqueous phase was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSC , and concentrated in vacuo to afford 8.14 grams of a clear amber oil. LCMS revealed a peak that was consistent with desired material. The material was absorbed onto silica gel and ran through an ISCO 80 gram column, eluting with CH2C12 / EtOAc. The broad peak looked to be a mixture of diastereomers in a ratio around 1.5:1. It was not determined which diastereomeric pair is the more predominant pair (0.988 g). The spiked shoulder from that broad peak looked to be a mixture of diastereomers in a ratio around 4: 1 (4.39 g).
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