New synthesis of oxcarbazepine via remote metalation of protected N-o-tolyl-anthranilamide derivatives

Lohse, Olivier; Beutler, Ulrich; Fünfschilling, Peter C.; Furet, Pascal; Kaufmann, Daniel; Penn, Gerhard; Zaugg, Werner

doi:10.1016/s0040-4039(00)01981-x

Cited by 37 publications

(16 citation statements)

References 10 publications

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“…In the absence of a DMG, path b predominates as the major reaction course to give dibenzazepinones 186. A recent application is the synthesis of oxcarbazepine (Trileptal, 187), presently the antiepileptic drug of choice, by Lohse et al [105] A combined aryl aminationDreM protocol was employed for its large-scale (200 mmol) preparation.…”

Section: Scheme 29 Synthesis Of Imelutein (135)mentioning

confidence: 99%

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

et al. 2004

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The concept of the complex-induced proximity effect (CIPE) in deprotonations is helpful in elucidating the mechanisms involved in carbanion chemistry and in planning organic syntheses. In this Review, the consequences of complexation of organolithium bases to functional groups of the substrates before the proton-transfer step are discussed. Experimental data from kinetic measurements and isotope-labeling experiments as well as the results of calculations in many cases point to a prelithiation complex as a reaction intermediate. Some examples from natural products synthesis illustrate how this concept can be used to obtain intermediates in a regio- or stereoselective manner. Of particular interest is the functionalization of positions that are remote from the coordination group.

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Section: Scheme 29 Synthesis Of Imelutein (135)mentioning

confidence: 99%

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

et al. 2004

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“…Hence, they envisaged the application of that methodology to the synthesis of OXC from suitably N-protected o-tolylanthranilamide derivatives, which were readily accessible from o-bromobenzamides 46a-b and o-toluidine 47 upon palladium-catalysed Scheme 17. N-arylation reaction conditions in good yields, as depicted in Scheme 18 [42]. The introduction of a removable protecting group in the amine moiety of the so-obtained o-tolylanthranilamide derivatives 48a-b was required prior to the remote metalation stage.…”

Section: Synthesis Of Oxc Via Remote Metalation and Cyclisationmentioning

confidence: 99%

Applications and Synthesis of the Antiepileptic Drug Oxcarbazepine and Related Structures

Carril

SanMartı́n²,

Domı́nguez

2007

COC

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Oxcarbazepine (OXC), the active ingredient of Trileptal ® (Novartis Pharma), has become the most widely prescribed drug for the treatment of epilepsy and other CNS diseases, due to its improved side-effect profile and relevant anticonvulsant activity compared to the parent drug, carbamazepine (CBZ). Given its importance and well-established therapeutic applications, much effort has been devoted to the improvement of its original synthetic protocol, searching for shorter, milder and more efficient routes, employing not only classical transformations but also modern synthetic tools, such as palladium-catalysed arylation reactions. In this article it is intended to resume the applications and features of OXC as an anticonvulsant drug, as well as to compile for the first time all the reported routes to OXC, from the originally-developed protocol to the latest methodology, which allowed for the synthesis of a family of structural analogues. Such synthetic sequences will be discussed and comprehensively classified according to whether the approach to OXC is based on either modifications on the iminodibenzyl ring or coupling reactions.

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“…ortho C anionic Fries equivalent of the aryl O-carbamate migration (Scheme 3E) [75c] and after N-methylation, 190 may be transformed into 1,2,3-trisubstituted systems 193 [76]. In another appealing manifestation of CIPE, the efficient conversion of 191 into dibenzazepinone 194 has been applied in an effective synthesis of the antiepileptic drug oxcarbazepine (Trileptal9) 195 [77] and may also be Scheme 47. Anionic pathways to oxindoles, anthranilates, and dibenzazepinones.…”

Section: Beyond Dom: the Directed Remote Metalation (Drem) Of Biaryl mentioning

confidence: 99%

The Directed ortho Metalation Reaction – A Point of Departure for New Synthetic Aromatic Chemistry

Hartung

Snieckus

2002

Modern Arene Chemistry

159

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After a brief allusion to the current status of synthetic aromatic chemistry, a tour based on the Directed ortho Metalation (DoM) strategy is provided with selections from recent literature which highlight a) the use of DoM for the regiospecific preparation of polysubstituted aromatics and heteroaromatics; b) the valuable symbiosis of DoM with transition metal catalyzed AraAr cross-coupling protocols; c) the extension of DoM to the Directed remote Metalation (DreM) concept in biaryls, which provides methodologies for the construction of condensed aromatics (fluorenones, phenanthrols) and heterocyclics (thioxanthones, xanthones, acridones, dibenzphosphorinones, dibenzthiepinone dioxides, dibenzoxepinones, dibenzazepinones, dibenzphosphinones); and d) the evolving links of DoM to other modern methodologies with a note on the DoM-Grubbs ring-closing metathesis connection. The presentation is solely methodologically rather than total synthesis oriented; dependable directed metalation groups (DMGs ¼ CONR 2 , OCONR 2 , SONR 2 , NHBoc), new and renewed, are emphasized; p-excessive (furan, thiophene, indole) and p-deficient (pyridine) heterocycle HetDoM chemistry is delineated. While definitely not comprehensive, this account attempts to give a flavor of current anionic aromatic chemistry in synthesis. 10.1Scheme 1. Synthetic approaches to substituted aromatics. 10.2 The DoM Reaction as a Methodological Tool 331 Scheme 3. DoM chemistry generalizations. 10.2 The DoM Reaction as a Methodological Tool 333 Scheme 5. The N-cumyl sulfonamide DMG. Scheme 6. The N-cumyl carbamate DMG. 10.2 The DoM Reaction as a Methodological Tool 335 Scheme 9. The di-tert-butyl phosphine oxide DMG. 10.3 Heteroaromatic Directed ortho Metalation (HetDoM) in Methodological Practice 337

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New synthesis of oxcarbazepine via remote metalation of protected N-o-tolyl-anthranilamide derivatives

Cited by 37 publications

References 10 publications

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

Applications and Synthesis of the Antiepileptic Drug Oxcarbazepine and Related Structures

The Directed ortho Metalation Reaction – A Point of Departure for New Synthetic Aromatic Chemistry

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