HK1182959A - Noribogaine compositions - Google Patents

Description

Noribogaine composition

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application No. 61/367,310 filed on 23/7/2010 and priority from U.S. provisional application No. 61/419,766 filed on 3/12/2010, both of which are hereby incorporated by reference in their entirety.

Technical Field

The present invention relates to noribogaine (noribogaine) compositions. In one embodiment, the noribogaine composition contains at least 95% noribogaine in the 2(R),4(S),5(S),6(S) and 18(R) enantiomeric form, and wherein the composition contains no more than 0.5wt% ibogaine (ibogaine) relative to the total amount of noribogaine. In another embodiment, the composition contains not more than 0.3wt% ibogaine relative to the total amount of noribogaine. In another embodiment, the composition contains not more than 0.1wt% ibogaine relative to the total amount of noribogaine.

Background

Noribogaine is a well known member of the alkaloid ibogaine family and is sometimes referred to as 12-hydroxyibogaine. Although U.S. patent No. 2,813,873 claims noribogaine as "12-O-desmethyl ibogaine," the structural formula of ibogaine provided by this U.S. patent is not correct. The structure of noribogaine has been determined and found to combine the features of tryptamine, tetrahydrohavine (tetrahydrohavine) and indoleazepine (indolazine). Noribogaine can be represented by the following general formula:

wherein the configuration of the atoms at the 2, 4, 5, 6 and 18 positions are 2(R),4(S),5(S),6(S) and 18 (R).

Recently, noribogaine and its pharmaceutically acceptable salts have received significant attention because non-addictive alkaloids are useful in treating drug dependence (U.S. Pat. No. 6,348,456) and are useful as potent analgesics (U.S. Pat. No. 7,220,737). Both of these U.S. patents are incorporated herein by reference in their entirety.

Noribogaine is typically prepared by O-demethylation of naturally occurring ibogaine:

the naturally occurring ibogaine is isolated from iboga (Tabernanth iboga), a shrub in western africa. Demethylation may be accomplished by conventional techniques, e.g., reaction with boron tribromide/dichloromethane at room temperature followed by conventional purification.

Ibogaine has hallucinogenic properties and is a class 1 controlled substance in the united states. Thus, the process for preparing noribogaine from ibogaine requires a high degree of assurance that unacceptable amounts of ibogaine contamination are avoided. However, there is no report that the noribogaine base so prepared is substantially free of ibogaine (e.g., no more than 0.5wt% relative to noribogaine). At best, U.S. patent No. 6,348,456 claims a substantially pure noribogaine compound, but does not disclose any purification method, let alone which substances the phrase "substantially pure" encompasses, and does not disclose the level of residual ibogaine in the composition. The synthesis of noribogaine from ibogaine is reported in U.S. patent No. 2,813,873. However, the' 873 patent also does not teach the purity of the noribogaine base obtained during its synthesis.

Accordingly, there is a need in the art to provide a noribogaine that is enantiomerically enriched (greater than 95% of the 2(R),4(S),5(S),6(S), and 18(R) enantiomers) and is substantially free of ibogaine (e.g., no more than 0.5wt% of ibogaine relative to the amount of noribogaine).

Disclosure of Invention

The present invention provides noribogaine compositions that are enantiomerically enriched and substantially free of ibogaine. Because the compositions do not contain unacceptable amounts of ibogaine and are enantiomerically enriched, the compositions make a significant breakthrough in treating addiction and/or pain.

In one aspect of the composition of the invention, the invention relates to a composition comprising noribogaine, wherein at least 95% of said noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers, and wherein said composition contains not more than 0.5wt% of ibogaine relative to the total amount of noribogaine.

In another aspect of the composition of the invention, the invention relates to a composition comprising noribogaine, wherein at least 95% of said noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers, and wherein said composition contains no more than 0.3wt% of ibogaine contamination relative to the total amount of noribogaine.

In some embodiments, the amount of ibogaine contained in the noribogaine composition is no more than 0.1wt% ibogaine relative to the total amount of noribogaine.

In some embodiments, at least 98%, preferably at least 99%, more preferably at least 99.5% of the noribogaine base is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers.

In some embodiments, the noribogaine of the present invention is bound to a solid support, optionally through a cleavable linker. The solid support may be a resin or beads.

Detailed Description

The present invention relates to compositions comprising noribogaine, and in particular, to compositions comprising highly pure noribogaine in the form of the 2(R),4(S),5(S),6(S) and 18(R) enantiomers. However, before describing the present invention in more detail, the following terms are first defined.

It is to be understood that this invention is not limited to particular embodiments described, and that changes may be made to particular embodiments of the invention. 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 appended claims.

It should 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 acceptable excipient" includes a plurality of such excipients.

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following terms used herein have the following meanings.

The term "comprising" or "comprises" as used herein means that the compositions and methods include the recited elements, but do not exclude other elements. When using "consisting essentially of … …" to define compositions and methods, it is meant to exclude other elements that have any essential significance to the combination for the purpose. Thus, a composition consisting essentially of the elements defined herein may not exclude other substances or steps that do not materially affect the basic and novel characteristics of the claimed invention. "consisting of … …" means that other components and substantial process steps are excluded in excess of trace elements. Embodiments defined by each of these conjunctive terms are within the scope of the invention.

The term "noribogaine" as used herein refers to the alkaloid noribogaine (including all enantiomers thereof), and the term "noribogaine" also includes various pharmaceutically acceptable salts thereof. Of particular note are enantiomers represented by the formula:

wherein the configuration of the atoms at the 2, 4, 5, 6 and 18 positions are 2(R),4(S),5(S),6(S) and 18 (R).

The term "solid support" refers to a substance having a rigid or semi-rigid surface that contains or is derivatizable to contain reactive functional groups that covalently attach the noribogaine base to its surface via a cleavable linker. Such materials are well known in the art and include, for example, silica, synthetic silicates, bioactivated silicates, porous glasses, hydrogels, silicate-containing minerals, synthetic polymers, polystyrene, polypropylene, polyethylene terephthalate,polyacrylamide, polyethylene glycol, polyacrylamide and its copolymers (including polystyrene/polyethylene glycol copolymers and polyacrylamide/polyethylene glycol copolymers), and the like. Other non-limiting examples of solid supports include: an anion exchange resin. These resins contain groups with a certain amount of positive charge and exchange anions. Non-limiting examples of anion exchange resins includeType I anion exchange resin,Type II anion exchange resin,Anion exchange resin of form I andtype II anion exchange resins.

The term "cleavable linking group" as used herein refers to a linking group that is a chemical or covalent group covalently attached at one end to a solid support and at the other end to a noribogaine base. At least one of the covalent bonds connecting the noribogaine to the cleavable linking group of the solid support can be readily cleaved by a specific chemical or enzymatic reaction, thereby providing a solid support-free noribogaine. The chemical or enzymatic reaction chosen to cleave the covalent bond of the linker arm is specific to the cleavage of the bond, thereby avoiding undesired reactions at other locations of the compound. The cleavable linking group is selected to correspond to the noribogaine formed on the solid support, thereby avoiding premature cleavage of the noribogaine from the solid support and not interfering with any steps used in the process of synthesis on the support. Suitable cleavable linking groups are well known in the art and may include groups such as carbonate groups, carbamate groups, amide groups, and the like. In a preferred embodiment of the present invention,the cleavable linking group contains no more than 10 atoms. More preferably, the cleavable linker contains 1 to 4 carbon atoms and 2 to 4 moieties selected from the group consisting of oxygen, nitrogen, sulfur, S (O) and S (O)₂A heteroatom of (a).

The term "reaction conditions" as used herein refers to the specific conditions under which a chemical reaction is carried out. Examples of reaction conditions include, but are not limited to, one or more of the following conditions: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants, presence of base or acid or catalyst, and the like. The reaction conditions for the known reactions are generally known to the person skilled in the art.

The term "reducing agent" as used herein refers to an agent that can donate electrons in a redox reaction, allowing hydrogen to be added to the molecule. Suitable reducing agents include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and the like.

The term "reductive amination conditions" as used herein refers to a reaction in which an amine and a carbonyl compound react to form an imine, followed by reduction of the imine to an amine using a reducing agent. The intermediate imine may be isolated and purified prior to the reduction step, or the intermediate imine may be used in the reduction step without prior isolation or purification.

The term "pharmaceutically acceptable salt" as used herein refers to salts that are pharmaceutically acceptable, non-toxic, derived from a variety of organic and inorganic counterions well known in the art, and includes, for example, counterions such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like when the molecule contains acidic functional groups and such counterions as chloride, bromide, tartrate, methanesulfonate, acetate, maleate, oxalate and the like when the molecule contains basic functional groups.

The term "protecting group" or "Pg" as used herein refers to the well-known functional groups: when attached to a functional group, the functional group renders the resulting protected functional group inert to the reaction conditions to be performed on the rest of the compound, and at a suitable time the functional group can react under "deprotection conditions" to regenerate the original functional group. The identity of the protecting groups is not critical and the protecting groups are selected to be compatible with the remainder of the molecule. In one embodiment, the protecting group is an "amino protecting group" that protects the amino functionality of ibogaine or noribogaine during the reaction described herein. Examples of conventional amino protecting groups include, for example, benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), and the like. In another embodiment, the protecting group is a "hydroxy protecting group" that protects the hydroxy functionality of the noribogaine base. Examples of hydroxyl protecting groups include, for example, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, dialkylsilyl ethers (e.g., dimethylsilyl ether), trialkylsilyl ethers (e.g., trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether), esters (e.g., benzoyl, acetyl, phenylacetyl, formyl, monohalo, bishalo, and trihaloacetyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl)) and carbonates (e.g., methyl, ethyl, 2,2,2, -trichloroethyl, allyl, benzyl, and p-nitrophenyl). Additional examples of hydroxyl protecting Groups can be found in standard references (e.g., Greene and Wuts, Protective Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons, and McOmie Protective Groups in Organic Chemistry,1975, Plenum Press). Methods for protecting and deprotecting the phenolic hydroxyl group of the compounds disclosed herein can be found in the art, and in particular, can be found in the Greene and Wuts writings, supra, and the references cited therein.

Preparation of noribogaine substantially free of ibogaine

The noribogaine compositions of the present invention may be prepared from ibogaine. Noribogaine containing no more than 0.5 ppm ibogaine can be prepared using solid support synthesis methods as described below. Since this compound is prepared from the natural product ibogaine, and the reactions described below do not involve any stereochemical centers, noribogaine so prepared may be at least 95% of the 2(R),4(S),5(S),6(S), and 18(R) enantiomers and possibly 100% of that enantiomer.

In the case of a solid support synthesis method using noribogaine, the noribogaine compositions of the present invention can be prepared from readily available starting materials using conventional methods and procedures as follows. It will be appreciated that where typical or preferred reaction conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressures, etc.) are given, other reaction conditions may also be used, unless otherwise specified. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Furthermore, it is obvious to the person skilled in the art that the usual protecting groups are necessary to avoid undesired reactions of the specific functional groups. Suitable protecting groups for a variety of different functional groups and suitable conditions for protecting and deprotecting a particular functional group are well known in the art. For example, many Protecting Groups are described in t.w.greene and g.m.wuts, Protecting Groups in organic Synthesis, fourth edition, Wiley, n.y.,2007, and references cited therein.

It has been discovered herein that noribogaine can be prepared and/or purified from ibogaine by using a solid support as shown in the schemes below, wherein PG represents an amine protecting group, LG represents a leaving group (e.g., a halogen or mesylate, tosylate, or such other group), L represents a cleavable linking group (e.g., a carbonyl compound such as a carbonate or carbamate), and the filled circles represent the solid support.

In the following schemes, O-demethylation of arylmethoxy groups to the corresponding phenols may be carried out using techniques known in the artBy any suitable method known. Suitable reagents include Lewis acids (e.g., BBr)₃，AlCl₃) Nucleophiles (e.g., RS-, N)₃SCN-), NaCN at high pH (e.g., pH 12), and the like. In some embodiments, O-demethylation should be performed under conditions that do not affect the attachment to the solid support or alter the stereochemistry of the stereochemical center of the molecule. Suitable agents can be readily determined by those skilled in the art and can be found, for example, in t.w.greene and g.m.wuts, Protecting Groups in Organic Synthesis, fourth edition, Wiley, n.y.,2007 (see, e.g., the reactivity tables (reactivitychart) in pages 1006 to 1008 and pages 1022 to 1032), and references cited therein.

Scheme 1

Noribogaine 5 can be prepared and purified from ibogaine 10 by any of the routes shown in scheme 1. Noribogaine (compound 5) differs from ibogaine in that the methoxy group of ibogaine is converted to a hydroxy group in noribogaine. In one embodiment, the indoleamine of ibogaine can be protected with an amine protecting group to produce compound 1, followed by simultaneous O-demethylation and removal of the protecting group (e.g., using) To produce noribogaine 5, or followed in sequence by O-demethylation and removal of the protecting group to produce noribogaine 5. Furthermore, in one embodiment, noribogaine can be directly prepared and purified by O-demethylation of ibogaine using methods known in the art, followed by purification of noribogaine by the following steps: the noribogaine base is added to the solid support (compound 12 or 13),washing to remove contaminants, cleaving the linking group L and recovering the noribogaine base 5. In the above synthetic methods, one or more of the noribogaine bases or intermediates shown above can be purified using standard purification techniques known in the art (e.g., column chromatography, HPLC, etc.). The compound of formula 11 is a commercially available or commercially available starting material (see, e.g., from Sigma)Commercial resins of (a) in one or two steps.

In another embodiment, noribogaine can be prepared and purified from ibogaine in the manner shown in scheme 2 below.

Scheme 2

Wherein Pg is hydrogen or an amino protecting group, and the filled circle represents a solid support.

Specifically, in scheme 2, amino-protected ibogaine (compound 1) is contacted with boron tribromide or other commonly used demethylating agent in, for example, dichloromethane, under conditions known in the art to produce amino-protected noribogaine (compound 2).

In scheme 2, the attachment of the amino-protected noribogaine (compound 2) to the solid support is accomplished by generating compound 4 using a chloroformate/solid support (compound 3) under conventional conditions, wherein the carbonate group is shown as a cleavable linking group for illustration only. Other cleavable linkers may likewise be used in scheme 2. Since amino-protected ibogaine does not contain a functional group that reacts with compound 3, only amino-protected noribogaine (compound 2) can react with a solid support and formCompound 4. Repeated washes of compound 4 can remove a portion of the amino-protected ibogaine that contaminates the amino-protected noribogaine sample used in the reaction. Furthermore, at any time, a small portion of the solid support may be removed, thereby providing a sample of noribogaine (after cleavage and deprotection). Subsequently, it can be determined by means such as GC/MS, NMR, C¹³-NMR and the like, to analyze the purity of the sample with respect to any ibogaine base present.

After a desired level of purity of noribogaine relative to any contaminating ibogaine is achieved, noribogaine can be recovered from the solid support by cleavage of the cleavable linker and subsequent deprotection of the amino group. Cleavage and deprotection are well known in the art.

As expected, a particularly pure noribogaine base (compound 5) can be obtained by repeating the following operations: forming amino-protected noribogaine (compound 2), binding compound 2 to the solid support via the hydroxyl group of the amino-protected noribogaine, and washing off a portion of the contaminating ibogaine from the solid support. This operation is repeated as many times as necessary and preferably no more than 5 times, and it has been found that noribogaine compositions containing no more than 0.5wt% of ibogaine relative to the amount of noribogaine present in the composition, noribogaine compositions containing no more than 0.3wt% of ibogaine relative to the amount of noribogaine present in the composition, or noribogaine compositions containing no more than 0.1wt% of ibogaine relative to the amount of noribogaine present in the composition can be prepared.

In another embodiment, the solid support is an anion exchange resin, wherein noribogaine base is ionically bonded to the anion exchange resin. Such a resin allows uncharged ibogaine to flow through the resin by simple elution. Non-limiting examples of anion exchange resins include solid supports, preferably selected from quaternary ammonium containing groups(e.g., trialkyl benzyl ammonium containing groups). Suitable trialkyl benzyl ammonium groups include trimethyl benzyl ammonium, dimethyl-2-hydroxyethyl benzyl ammonium, and the like. Non-limiting examples of commercially available anion exchange resins includeType I anion exchange resin,Type II anion exchange resin,Anion exchange resin of form I andtype II anion exchange resins. The recovery of noribogaine base by pH adjustment is well known to those skilled in the art.

Alternatively, as shown in scheme 3 below, noribogaine hydrochloride is prepared from ibogaine hydrochloride by the following steps: ibogaine hydrochloride is first converted to ibogaine base free base, treated with methanol, and subsequently treated with a base such as potassium carbonate in a solvent such as dichloromethane. Ibogaine is then converted to noribogaine hydrobromide by: treatment with boron tribromide or other commonly used demethylating agents in a solvent such as dichloromethane, followed by quenching with methanol, yields noribogaine hydrobromide. The noribogaine base hydrobromide is then converted to the free base by treatment with a base such as potassium carbonate in a solvent such as dichloromethane, followed by purification over silica, and then converted to the hydrochloride salt using HCl in a solvent such as isopropanol.

Scheme 3

Another method of demethylation is also accomplished as shown in scheme 4 below.

Scheme 4

The present inventors have found that BCl is used₃Substitute for BBr₃The removal of methyl ether has many advantages. For example, using BCl₃The noribogaine hydrochloride salt is formed in one step without the need to use BBr₃The noribogaine hydrobromide obtained was converted to the hydrochloride. Furthermore, the present invention finds the use of BCl₃Substantially reduce the use of BBr₃Halogenation of the resulting aromatic ring.

In one embodiment, the amount of ibogaine in the noribogaine composition can be determined by initiating formation on ibogaine¹⁴C-rich methoxy groups. Against background in the final composition¹⁴The amount of C may be corrected to the amount of ibogaine in the noribogaine composition, which may then be used to verify whether the synthesis step used is under conditions that allow for a maximum amount of ibogaine in the noribogaine composition or under conditions that are below the allowed maximum amount of ibogaine in the noribogaine composition. Ibogaine on¹⁴The methoxy group enriched in C can be easily passed through¹⁴C-enriched methylating agent methylating the 12-hydroxy group of noribogaine. For determining in the composition¹⁴Techniques for the amount of C are well known in the art and detection limits are below 1 ppt.

It will be apparent to those skilled in the art that many changes can be made in the above exemplary methods (both raw materials and methods) without departing from the scope of the invention.

The following synthetic examples and biological examples are provided to illustrate the present invention and are not to be construed as limiting the scope of the present invention in any way. All temperatures are in degrees celsius unless otherwise indicated.

Composition of noribogaine

The present invention provides noribogaine compositions that are enantiomerically enriched and substantially free of ibogaine.

In one embodiment, the present invention provides a composition comprising noribogaine, wherein at least 95% of said noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers, and wherein said composition comprises no more than 0.5wt% of ibogaine relative to the total amount of noribogaine. In another embodiment, the composition comprises not more than 0.3wt% ibogaine relative to the total amount of noribogaine. In another embodiment, the composition comprises not more than 0.1wt% ibogaine relative to the total amount of noribogaine.

In another embodiment, the present invention provides a composition comprising noribogaine, wherein at least 98% of said noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers, and wherein said composition comprises no more than 0.5wt% of ibogaine relative to the total amount of noribogaine. In another embodiment, the present invention provides a composition comprising noribogaine, wherein at least 98% of said noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers, and wherein said composition comprises no more than 0.3wt% of ibogaine relative to the total amount of noribogaine. In another embodiment, the composition comprises not more than 0.1wt% ibogaine relative to the total amount of noribogaine.

Examples

In the following examples, abbreviations have their generally accepted meaning.

Example 1 Synthesis and purification of noribogaine from ibogaine

Example 1 illustrates a method for synthesizing and purifying noribogaine from ibogaine, as shown in scheme 5 below:

scheme 5

Specifically, in scheme 5, ibogaine base is contacted with a stoichiometric excess of benzylchloroformate in an inert solvent such as methylene chloride. The reaction mixture also contains at least a stoichiometric equivalent of diisopropylethylamine relative to ibogaine base to remove acid formed during the reaction. The reaction is maintained under an inert atmosphere at room temperature until substantial completion as evidenced by, for example, thin layer chromatography. At this point, an O-demethylating agent (e.g., boron tribromide or aluminum trichloride) or, preferably, a stoichiometric excess of the O-demethylating agent is added to the reaction mixture, which is then maintained under conditions (e.g., room temperature conditions) such that the methoxy group of ibogaine has been converted to the hydroxy group of noribogaine.

The hydroxyl groups generated as described above are then used as complementary functional groups for attachment to a solid support. Specifically, the excess chloroformate bound to the solid support is combined with N-CBz-noribogaine base under conventional conditions that allow carbonate linkages to form. Chloroformates bound to a solid support can be obtained commercially from a polymer support bearing hydroxyl groups (e.g., hydroxymethylpolystyrene or polymer-bound benzyl alcohol, all of which are commercially available) And carbonyldichloride. Since CBz-ibogaine base does not readily react under these O-demethylation conditionsAccordingly, it may remain in the solution phase of the reaction mixture and may be washed out of the reaction mixture by conventional techniques including placing the solid support in a column and flowing excess solvent through the column.

In one embodiment, 1kg of a solid support containing CBz-noribogaine is loaded onto a column. The plug of the column was partially opened so that the flow rate through the column was maintained at 0.5 l/h. Dichloromethane was continuously added to the top of the column and recovered at the bottom of the column. The recovered dichloromethane was removed to yield residual CBz-ibogaine base. A portion of the solid support was then loaded into the hydrogenation vessel along with methanol and a catalytic amount of palladium-carbon. The hydrogenation is carried out continuously under elevated pressure for about 5 hours. The reaction was then stopped and methanol was recovered and removed to yield noribogaine. Additional purification of noribogaine base can be accomplished by HPLC as desired.

Example 2 Synthesis and purification of noribogaine hydrochloride from ibogaine hydrochloride

Scheme 6

Step 1 purification of crude ibogaine hydrochloride and liberation of ibogaine free base from the purified starting material

A10L flange reactor was charged with ibogaine (428.5 g) and ethanol (4.30L) under nitrogen. The resulting suspension was heated to 65 ℃ to 75 ℃ for 1 hour 20 minutes and cooled to room temperature with stirring overnight. A whitish, pale yellow suspension was obtained. The solid was collected by filtration and washed with dichloromethane (DCM, 2 × 0.5L). The filter cake was dried under nitrogen to constant weight (279 g). The solid was stored under nitrogen and light was denied for 5 days. Process Control (IPC) of High Performance Liquid Chromatography (HPLC) showed ibogaine (97.38%), ibogaine (2.31%) and ibogaine (0.31%). The filtrate was concentrated to dryness in vacuo to give a light brown solid (72 g). IPCs for HPLC showed ibogaine (59.49%), ibogaine (17.31%) and ibogaine (20.12%) as well as the unknowns (3.04% total). Purified ibogaine hydrochloride (279 g, 97.38%) was suspended under nitrogen in DCM (2.85L). A25 wt% aqueous solution of potassium carbonate (470 ml) was added and the phases were mixed vigorously for 10 minutes. The phases were separated. The aqueous layer was extracted with DCM (2X 720 ml). The aqueous layer was discarded. The combined organic phases were washed with water (0.73L), the washed organic phase was separated into two substantially equal portions and concentrated in vacuo at 50 ℃ to give a light brown foam. The foam was dried under vacuum to constant weight. IPCs by HPLC showed ibogaine (93.15%), ibogaine (2.28%), ibogaine (0.31%) and the unknown (4.26% total).

Step 2, converting free base of ibogaine into hydrobromide of noribogaine

A3L flanged flask equipped with a thermometer, gas bubbler, overhead stirrer, Schott addition bottle and scrubber was charged with dichloromethane (400 ml) and BBr under nitrogen₃Dichloromethane (1M, 368 ml). The mixture was cooled to 0 ℃ to 5 ℃ with stirring. A Schott bottle was charged with ibogaine base free base (75 g, MLR/629/73-1) and dichloromethane (300 ml) to give a light brown solution. Nitrogen was passed into the bottle, which was covered with foil and connected to the flange reactor via a pressure loading line. The solution was slowly added to the reactor over 110 minutes. After loading, a suspension is formed. When the loading was complete, the contents of the reactor were allowed to warm to room temperature overnight. The mixture was cooled to 0 to 5 ℃ and quenched with methanol, and the mixture was allowed to warm to room temperature and stirred overnight. The solid was collected by filtration, washed with DCM and dried (yield: 81%).

0054 Ibogatran base free base and BBr₃The reaction of (a) produces brominated by-products, which can be formed by using BCl₃Substitute for BBr₃To avoid, BCl₃The corresponding HCl salt is formed directly.

Step 3. conversion of noribogaine hydrobromide to noribogaine hydrochloride

A10L flange separatory funnel equipped with a nitrogen inlet, gas bubbler, overhead stirrer, thermometer, and dropping funnel was charged with noribogaine base hydrobromide (214.35 g), MeOH (1.95L), and dichloromethane (4.18L) to give a suspension. K dissolved in water (1.65L) was added over 1 hour with stirring and nitrogen₂CO₃(234 g, 3.0 equivalents). During the addition, the internal temperature rose from 18.9 ℃ to 23.2 ℃. Stirring was continued until a two-phase system was obtained. The lower organic phase was separated. The upper aqueous phase was extracted with dichloromethane (2X 1.46L). The combined organic phases were washed with water (1X 1.95L). The organic layer was divided into two portions and each portion was concentrated to dryness in vacuo to afford a light brown solid (1X 88.9g, 1X 79.3). The solid was purified by chromatography using flash silica gel (7.20 kg, 43wt eq), eluting with dichloromethane/acetonitrile/triethylamine (1: 1: 0.5) to collect a total of 16 fractions (5L each), of which fractions 5 to 16 showed the desired product by TLC and HPLC. Based on the results of the test work on salt formation, fractions 7 to 11 were combined and concentrated to dryness to give a beige solid (136 g). The solid was charged to a 5L flanged flask equipped with a nitrogen inlet, gas bubbler, overhead stirrer, dropping funnel and thermometer. Isopropanol (3.27L) was added and the mixture was heated to 45 to 55 ℃ over 1 hour with stirring and nitrogen to give a clear solution. Isopropanol/HCl (5M, 128.6ml, 1.4 equiv.) was added over 1 hour. An off-white solid was observed to precipitate and the suspension was cooled to room temperature overnight with stirring. The mixture was cooled to 0 ℃ to 5 ℃. After 30 minutes, the solid was collected by filtration and washed with dichloromethane (2X 0.49L) and dried under suction under nitrogen to constant weight. The solid was dried under vacuum at 60 ℃ for 4 more days.

The yield of noribogaine free base was 168.2g (99%), the yield of noribogaine free base (purified) was 136g (81%), and the yield of noribogaine hydrochloride was 150g (98%). The overall yield (based on free base formation, purification and salt formation steps) was 79%. The analytical results were as follows: before final drying, noribogaine hydrochloride (99.3%), byproduct (0.5%) and ibogaine (0.1%) were present. After 3 days of drying, noribogaine hydrochloride (99.10%), byproducts (0.33%), ibogaine (0.07%), ibogaine (0.08%), and unknowns (0.42% in total) were contained. Another batch contained noribogaine hydrochloride (99.34%), ibogaine (0.02%), ibogaine (< 0.01%) and ibogaine (0.02%).

The above method shows that noribogaine substantially free of ibogaine is prepared according to the present invention. Although this method provides noribogaine that is substantially free of ibogaine, small amounts of ibogaine (about 0.02wt% or 200ppm of noribogaine) are still observed in noribogaine thus prepared by ibogaine.

Claims (12)

1. A composition comprising noribogaine, wherein at least 95% of said noribogaine is present as the 2(R),4(S),5(S),6(S), and 18(R) enantiomers, and wherein said composition contains no more than 0.5wt% ibogaine relative to the total amount of noribogaine.

2. The composition of claim 1, wherein the composition contains not more than 0.3wt% ibogaine relative to the total amount of noribogaine.

3. The composition of claim 1, wherein the composition contains not more than 0.1wt% ibogaine relative to the total amount of noribogaine.

4. The composition of claim 1, wherein the composition contains less than 800ppm ibogaine base.

5. The composition of claim 1, wherein at least 98% of the noribogaine is present as the 2(R),4(S),5(S),6(S) and 18(R) enantiomers.

6. A composition comprising noribogaine, wherein at least 98% of said noribogaine is present as the 2(R),4(S),5(S),6(S), and 18(R) enantiomers, and wherein said composition contains no more than 0.5wt% ibogaine relative to the total amount of noribogaine.

7. The composition of claim 6, wherein the composition contains not more than 0.3wt% ibogaine relative to the total amount of noribogaine.

8. The composition of claim 6, wherein the composition contains not more than 0.1wt% ibogaine relative to the total amount of noribogaine.

9. A composition comprising noribogaine hydrochloride and isopropanol.

10. A composition comprising noribogaine, hydrochloric acid at a concentration of 5M and isopropanol, wherein the temperature of the composition is from 45 ℃ to 55 ℃.

11. A composition comprising noribogaine, silica gel, dichloromethane, acetonitrile, and an organic base.

12. A composition comprising solid noribogaine hydrochloride and isopropanol.