Beispiel für die Evolution der Synthese eines Entwicklungsproduktes: Herstellung des als 5 HT2C/2B-Receptor-Antagonisten wirksamen Indolo-naphthyridin-Derivates SDZ SER-082 in enantiomerenreiner Form

cis-4,5,7a,8,9,10,11,11a-Octahydro-7H-10-methylindolo[1,7-bc][2,6]naphthyridine (rac-4) (SDZ SER-082) is a selective and potent 5-HT2C/2B receptor antagonist, exerting weak affinity towards the 5-HT2A receptor site. The compound 4 was found to be a potential development candidate in several CNS indications. The key step in the initial synthesis was the photocyclization of the indolyl tetrahydropyridino-carbamic acid ethyl ester 1 to afford the cis/trans-naphthyridine 2/3. This process turned out to be inefficient for a scale-up. Three alternative synthetic routes A, B and C are discussed: The 'Imino-Diels-Alder' reaction applying indoline/formaldehyde/cyclopentadiene (route A) and the intramolecular Heck cyclization of 7-bromo-2,3-dihydro-1-[(1,2,5,6-tetrahydro-1-methyl-4-pyridyl)-carbonyl]-1H -indole (10) (route B) were surpassed in their synthetic efficiency by the Friedel-Crafts cyclization of 4-(2,3-dihydroindole-1-carbonyl)-1-methylpiperidin-3-one (16) (route C), followed by reduction to give rise to the racemic naphthyridine rac-4. It was subjected to resolution by applying a kg scale repetitive chromatography on a chiral stationary phase to give (+)-(7aS,11aR)-4 in over 90% yield and 99.9% enantiomeric purity.