Synthesis of Tegoprazan
Chemical synthesis of Tegoprazan, a drug discovered by Pfizer and developed by RaQualia Pharma and CJ Healthcare for the treatment of gastroesophageal reflux disease (GERD). In 2018 its commercial use was approved in Korea.
Synthesis of building block #1:
1. Selective O-benzylation.
2. Regioselective bromination with NBS.
3. Acetylation of aniline.
4. Pd-catalyzed cyanation of the aryl bromide.
5. Iron mediated reduction and concomitant condensation with the proximal N-acetyl functionality.
6. Hydrolysis of the nitrile.
7. Coupling of the resulting carboxylic acid with the amine.
8. Protection of the amine with tosyl.
9. Removal of the benzyl group via hydrogenolysis.
Synthesis of building block #2:
1. Condensation with the alkyne.
2. Reduction of the double bond and Friedel-Crafts acylation.
3. Corey-Bakshi-Shibata reaction.
Synthesis of Tegoprazan:
10. Mistunobu-type reaction; SN2.
11. Removal of the tosyl group.
Reference work: