Practical Large-Scale Preparation of (R)-Rolipram Using Chiral Nickel Catalyst

Abstract

Antidepressant drug (R)-rolipram was readily prepared on a large scale from isovanilline via a succinct route. The key reaction was carried out using a 1 mol% loading of nickel(II)-bis[(S,S)-N,N′-dibenzylcyclohexane-1,2-diamine]Br₂ complex as the catalyst. The ee% could reach to 99%, and the catalyst could be recovered and used in the next reaction cycle with high ee%.

GRAPHICAL ABSTRACT

Keywords:

• Asymmetric synthesis
• Michael addition
• (R)-rolipram

Notes

^a All the reactions stopped with conversion of more than 99%.

^b Isolated yield.

^c Enantiomeric excess was determined by HPLC with chiracel AD column.

^d Neat reaction with 1.5 equivalent of diethyl malonate.

^a Isolated yield.

^b Enantiomeric excess was determined by HPLC with chiracel AD column.