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Methods and Compositions for Preparing Noribogaine from Voacangine

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Methods and Compositions for Preparing Noribogaine from Voacangine (19) & (11) EP 2 481 740 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 01.08.2012 Bulletin 2012/31 C07D 487/18 (2006.01) (21) Application number: 11159572.4 (22) Date of filing: 24.03.2011 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Mash, Deborah C. GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Miami, FL 33137 (US) PL PT RO RS SE SI SK SM TR • Gless, Richard D. Designated Extension States: Miami, FL 33137 (US) BA ME • Moriarty, Robert M. Miami, FL 33137 (US) (30) Priority: 26.01.2011 US 436511 P 17.03.2011 US 453884 P (74) Representative: Gibson, Mark 21.03.2011 US 454904 P Sagittarius IP Taylor House (71) Applicant: DemeRx, Inc. 39 High Street Miami, FL 33137 (US) Marlow Buckinghamshire SL7 1AF (GB) (54) Methods and compositions for preparing noribogaine from voacangine (57) Disclosed are methods and compositions for preparing and purifying the non-addictive alkaloid noribogaine. EP 2 481 740 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 481 740 A1 Description Field of the Invention 5 [0001] This invention relates generally to methods and compositions for preparing and purifying the non-addictive alkaloid noribogaine. State of the Art 10 [0002] Noribogaine is a well known member of the ibogaine family of alkaloids and is sometimes referred to as 12- hydroxyibogaine. US Patent No. 2,813,873 claims noribogaine albeit as "12-O-demethylibogaine" while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tyrptamine, tetrahydrohavaine and indolazepines. Noribogaine can be depicted by the following formula: 15 20 25 [0003] Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non- addictive alkaloid useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737). [0004] Conventionally, noribogaine is prepared by demethylation of naturally occurring ibogaine: 30 35 which is isolated from Tabernanth iboga, a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional 40 purification. Alternatively, noribogaine can be prepared from the naturally occurring alkaloid, voacangine 45 50 by decarboxylation followed by demethylation as described in U.S. Patent No. 2,813,873. Such a process provides for ibogaine as the first intermediate in this two step synthesis. [0005] Ibogaine is addictive and possesses hallucinogenic properties. It is a Schedule 1-controlled substance as 55 provided by the US Food and Drug Administration. Accordingly, methods for preparing noribogaine from ibogaine require high levels of assurance that contamination with unacceptable levels of ibogaine is avoided. As above, a one-step method for preparation of noribogaine from ibogaine via demethylation does not provide the requisite assurance that ibogaine will consistently be removed as a potential contaminant. This applies equally as well to noribogaine prepared 2 EP 2 481 740 A1 from voacangine as described above as the penultimate compound in this synthesis is ibogaine. [0006] Accordingly, there is an ongoing need to provide a method for preparing noribogaine from voacangine such that the potential for ibogaine contamination can be effectively and reliably minimized. 5 Summary of the Invention [0007] This invention provides methods and compositions for the preparation of noribogaine wherein contamination by ibogaine is predictably and effectively minimized, if not altogether eliminated. In certain embodiments, this invention employs the use of solid supports to effect separation of noribogaine from any possible contaminants such that any 10 ibogaine contamination issignificantly reduced if not altogethereliminated. In certainembodiments, this inventionemploys an ion exchange resin to effect separation of noribogaine from any possible contaminants such that any ibogaine con- tamination is significantly reduced if not altogether eliminated. [0008] Accordingly, in one of its method aspects, this invention is directed to a method for preparing noribogaine which method comprises: 15 a) converting voacangine to 12-hydroxyibogamine-18-carboxylic acid or the carboxylic acid salt or ester thereof, wherein the indole nitrogen is optionally protected by an amino protecting group; b) optionally isolating the 12-hydroxyibogamine-18-carboxylic acid or the carboxylic acid salt, ester and/or amino protected derivative thereof; 20 c) converting the product of step a) or b) to noribogaine; and d) isolating noribogaine. [0009] In another of its method aspects, this invention is directed to a method for preparing noribogaine which method comprises: 25 a) converting voacangine to 12-methoxyibogamine-18-carboxylic acid or the carboxylic acid salt or ester thereof, wherein the indole nitrogen is optionally protected by an amino protecting group; b) optionally isolating the 12-methoxyibogamine-18-carboxylic acid or the carboxylic acid salt, ester and/or amino protected derivative thereof; 30 c) converting the product of step a) or b) to noribogaine; and d) isolating noribogaine. [0010] In another of its method aspects, this invention is directed to a method for preparing noribogaine which method comprises: 35 a) converting voacangine to 12-hydroxyibogamine-18-carboxylic acid the carboxylic acid salt thereof, wherein the indole nitrogen is optionally protected by an amino protecting group; b) converting the 12-hydroxyibogamine-18-carboxylic acid or the carboxylic acid salt and/or amino protected deriv- ative thereof to noribogaine; and 40 c) isolating noribogaine. [0011] In another of its method aspects, this invention is directed to a method for preparing and purifying noribogaine which method comprises: 45 a) converting voacangine to 12-hydroxyibogamine-18-carboxylic acid methyl ester wherein the indole nitrogen is optionally protected by an amino protecting group; b) optionally covalently attaching 12-hydroxyibogamine- 18-carboxylic acid methyl ester or amino protected derivative thereof to a solid support via the hydroxyl group of 12-hydroxyibogamine-18-carboxylic acid methyl ester or amino protected derivative thereof so as to form a suspension of solid supports having 12-hydroxyibogamine-18-carboxylic 50 acid methyl ester or amino protected derivative thereof bound thereto; c) removing residual voacangine from said suspension; d) cleaving and recovering the 12-hydroxyibogamine-18-carboxylic acid methyl ester or amino protected derivative thereof from the solid support; e) converting the 12-hydroxyibogamine-18-carboxylic acid methyl ester or amino protected derivative thereof to 55 noribogaine; and f) isolating noribogaine. [0012] In another of its method aspects, this invention is directed to a method for preparing and purifying noribogaine 3 EP 2 481 740 A1 which method comprises: a) covalently attaching voacangine to a solid support via the indole nitrogen of voacangine so as to form a suspension of solid supports having voacangine bound thereto; 5 b) converting voacangine to 12-hydroxyibogamine-18-carboxylic acid methyl ester or 12-hydroxyibogamine-18- carboxylic acid or carboxylic acid salt thereof under conditions wherein the level of voacangine bound to the solid support is less than 0.1 weight percent; c) cleaving and recovering 12-hydroxyibogamine-18-carboxylic acid methyl ester or 12-hydroxyibogamine-18-car- boxylic acid or carboxylic acid salt thereof from the solid support; 10 d) converting the 12- hydroxyibogamine-18-carboxylic acid methyl ester or 12-hydroxyibogamine-18- carboxylic acid or carboxylic acid salt thereof to noribogaine; and e) purifying noribogaine. [0013] In another of its method aspects, this invention is directed to a method for preparing and purifying noribogaine 15 which method comprises utilizing an ion exchange resin for isolating and/or purifying the 12-hydroxyibogamine-18- carboxylic acid methyl ester, 12-hydroxyibogamine-18-carboxylic acid or carboxylic acid salt thereof, or noribogaine or a corresponding salt thereof. [0014] In one of its composition aspects, this invention is directed to a solid support having voacangine, 12- hydroxy- ibogamine-18-carboxylic acid methyl ester or 12-hydroxyibogamine-18-carboxylic acid or carboxylic acid salt thereof 20 covalently bound thereto through a cleavable linker. Detailed Description of the Invention [0015] This invention is directed to methods and compositions comprising noribogaine and, in particular, methods and 25 compositions comprising highly pure noribogaine. However, prior to describing this invention in greater detail, the following terms will first be defined. [0016] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the 30 appended claims. [0017] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutically ac- ceptable excipient" includes a plurality of such excipients. 35 1. Definitions [0018] Unless defined otherwise,
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