An Efficient and Cost-Effective Synthesis of Pagoclone

Abstract

The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA A receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a β-keto phosphonium salt was prepared by selectively reacting a primary r-bromo ketone with triphenylphosphine in the presence of a secondary r-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a γ-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.

Asymmetrische Brønsted‐Säure‐katalysierte Synthese von Isoindolinen: Steigerung des Enantiomerenverhältnisses durch stereoablative kinetische Racematspaltung

“…[5] Der Zugang zu 1-und 1,3-substituierten Isoindolinen 4 und 5 wird durch die Tatsache erschwert, dass es nur eine beschränkte Zahl von Verfahren zur Synthese dieser Verbindungen gibt. [6] Darüber hinaus gibt es nur wenige Methoden zur Herstellung enantiomerenreiner Isoindoline.…”

On the Importance of the Nature of Hydrogen Bond Donors in Multiple Hydrogen Bond Systems

“…[11] This tosylate was prepared according to a preparation published by Le Mest. [11] 14 was obtained according to the literature: 2-amino-7-hydroxynaphthyridine was synthesized according to a procedure published by Stuk [13] and this was converted by a preparation of Newkome [14] to 2,7-dihydroxynaphthyridine and after chlorination to 14. Anhydrous ethanol was obtained by refluxing with sodium and diethyl phthalate (1 h) followed by distillation.…”

“…Naphthyridine 13 was synthesized by the reaction of known [13,14] dichloronaphthyridine 14 with n-butylamine in 68 % yield (Scheme 2). Also in this example, the N-H donor in the amides 2 is more acidic than the amine N-H atoms in 13, and thus larger binding constants have been found for the more acidic amide system than for the amine.…”

“…Column chromatography [silica gel, cyclohexane/ethyl acetate (1:1), R f = 0.22] yielded 9 as a colorless oil (22.7 g, 92 % yield). 13 [20] 70 5 -10-250 20 ): t ret = 17.8 min, purity: 99 %.…”

“…13 C NMR (75.5 MHz, CDCl 3 , 25°C): δ = 15.0 (q, 13-C), 25.1 (t, 3-C), 43.9 (t, 2-C), 66.5 (t, 12-C), 68.8 (t, 4-C), 69.7 (t, 6-C), 70.1 (t, 7-C), 70.4 (t, 9-C), 70.6 (t, 10-C), 173. (14,4.00 g, 20.0 mmol) was dissolved in n-butylamine (65 mL) and heated at 78°C for 18 h. After cooling, the solvent was removed and the residue was dissolved in dichloromethane (25 mL) and water (25 mL).…”