New Synthetic Route to (1S)-4,5-Dimethoxy-1-[(methylamino)methyl] Benzocyclobutane,a Key Intermediate of Ivabradine |
| |
| Authors: | Xin Liu Yu Liu Huili He Zhan Cai |
| |
| Institution: | 1. State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China;2. State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , P. R. China;3. Novel Technology Center of Pharmaceutical Chemistry , Shanghai Institute of Pharmaceutical Industry, Shanghai Engineering, Research Center of Pharmaceutical Process , Shanghai , P. R. China |
| |
| Abstract: | An efficient process for the preparation of (1S)-4,5-dimethoxy-1-(methylamino)methyl] benzocyclobutane (S)-3 as ivabradine intermediate, which was obtained in 56% yield, is described. The salient feature of this process is the racemization of the undesired (1R)-4,5–dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (R)-12, and the overall yield of (S)-12 was improved to 70% by three resolutions of the racemized acid with R-(α)-phenylethanamine. The reduction of amide (S)-13 was achieved with NaBH4-I2 in refluxing tetrahydrofuran, giving the corresponding amine (S)-3 in 90% yield. The improved synthetic route described herein is cost-efficient, environmentally friendly and feasibile for scale-up production. Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] |
| |
| Keywords: | Benzocyclobutane ivabradine reduction resolution |
|
|
