A New Industrial Process for Oxcarbazepine

Abstract

A novel industrial process for the antiepileptic drug oxcarbazepine 1 has been developed. Unlike the old process, the new process is free from halogenated solvents and can be performed in standard production equipment. It starts from commercially available 1,3-dihydro-1-phenyl-2H-indol-2-one 10. In the key step, an electrophilic ring closure reaction of 2-[(methoxycarbonyl)phenylamino] benzeneacetic acid 5 to 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxylic acid methyl ester 6 in poly phosphoric acid was applied. For the manufacture of 5, a highly efficient process using a dianion strategy was developed.

5-(Prop-2-ynyl)-5H-dibenzo[b,f]azepine

“…For the biological activities of iminostilbene, see: Kumar & Naik (2010); Balaure et al (2009) ;Bhatt & Patel (2005); Fuenfschilling et al (2005); Rosowsky et al (2004); Brzozowski & Saczewski (2002); Kulkarni et al (1991); Arya et al (1977). For the crystal structures of the closely related compounds, see: Jayasankar et al (2009) ;Nagaraj et al (2005); Sadashiva et al (2005).…”

Applications and Synthesis of the Antiepileptic Drug Oxcarbazepine and Related Structures

“…The most commonly employed synthetic approach to 6 implied a three step sequence starting from commercially available o-nitrotoluene 8 [25]. The first step of such sequence involved an oxidative coupling reaction mediated by oxygen and potassium tertbutoxide.…”

“…The originally employed synthetic route for the manufacture of OXC at Novartis Pharma was a combination of some of the strategies described thus far, which were regarded as more advantageous in terms of cost, safety and yield [25]. Such combination of methodologies, which is depicted in Scheme 17, has been used until somewhat recently in industry, before being replaced by the improved current protocol that will be disclosed in the next section.…”

“…Treatment with phosgene, followed by methanolysis and hydrolysis of the methyl ester moiety afforded target carboxylic acid 60a. Despite the overall yield was good, the route held several drawbacks, such as excessive length and use of toxic reagents, which were lately overcome by introducing carbamate moiety directly on dianion 67, obtained from sodium carboxilate 63 upon treatment with BuLi, successfully affording target 60a in three steps (Scheme 22) [25,43].…”

Drug Discovery in Epilepsy: A Synthetic Review

“…Iron-catalyzed reduction and acidic hydrolysis (Methods E and F) were the key steps in these synthetic sequences (Aufderhaar, 1981;Eidenhammer et al, 2000). The latter approaches are related to the originally employed industrial procedure at Novartis (Fuenfschilling et al, 2005 Scheme 3. Other synthetic sequences leading to carbamazepine and oxcarbazepine.…”