反应详情

温度

-80 °C

145 mg of 4-(4-fluorobenzoyl)-3-hydroxymethyl-benzonitrile (0.56 mmol, 1.0 eq.) and 100 mg of 1S,2R—N-methylephedrine 99% (0.56 mmol, 1.0 eq.) are dissolved in a two-necked round bottomed flask in 3 mL of toluene under an inert atmosphere (N2). At room temperature, 160 μL of diisopropoxymethyl borane (0.59 mmol, 1.05 eq.) is added. The reaction mixture is brought to 70° C. and stirred at this temperature for 30 minutes. The solvent is gently removed under reduced pressure within 15 minutes. 3 mL of toluene is added and the reaction mixture is cooled to −80° C. 800 μL (2 eq.) of a 1.3M solution of dimethylaminopropyl magnesium chloride in THF is slowly added (duration: 2 minutes). Stirring is continued for 10 minutes at −80° C. HPLC control indicated a conversion of >90%. The ratio of S-diol (4-[(S)-4-dimethylamino-1-(4-fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) to R-diol (4-[(R)-4-dimethylamino-1-(4-fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) is 71.6:28.4 (enantiomeric excess=43.2%). About 10% of 4-[(4-fluorophenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile are formed as a byproduct.

1. customis brought to 70° C.
2. customThe solvent is gently removed under reduced pressure within 15 minutes
3. addition3 mL of toluene is added
4. addition800 μL (2 eq.) of a 1.3M solution of dimethylaminopropyl magnesium chloride in THF is slowly added (duration: 2 minutes)
5. stirringStirring
6. waitis continued for 10 minutes at −80° C