DESC:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of tetrabenazine having desired purity. Specifically, the invention relates to a process for preparing tetrabenazine (1) comprising reaction of acid addition salt of the key intermediate,
3-(dimethylamino)methyl-5-methylhexan-2-one with 6,7-dimethoxy-3,4-dihydroiso- quinoline hydrochloride in presence of an organic acid to give the compound of formula (1) conforming to regulatory specifications.

BACKGROUND OF THE INVENTION

Tetrabenazine of formula (1), chemically known as cis rac-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one belongs to the class of tetrahydroisoquinoline compounds, which are known to possess varied biological activities. Tetrabenazine, which is used in the symptomatic treatment of hyperkinetic movement disorder, is marketed under the brand name Nitoman in Canada and Xenazine in New Zealand as well as some parts of Europe. Tetrabenazine is approved by USFDA on Aug.15, 2008 under the brand name Xenazine for the treatment of chorea associated with Huntington's disease (HD).

Tetrabenazine (1)
Tetrabenazine (1) was first disclosed in US 2,830,993 wherein the synthetic sequence involves reaction of isoquinoline derivatives with malonic acid esters, followed by cyclization of the appropriately substituted intermediates to furnish the desired tricyclic compound. The synthetic method disclosed in US 2,830,993 comprises reaction of 3,4-dimethoxyphenylethylamine (P-1) with ethyl malonyl chloride to furnish 1-carbethoxymethyl-6,7-dimethoxy-3,4-dihydroisoquinoline (P-3). Raney nickel hydrogenation of (P-3), followed by reaction of the resultant tetrahydro isoquinoline derivative (P-4) with mono-isobutyl malonic acid dimethyl ester and paraformaldehyde provides 1-carbethoxymethyl-2-(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (P-6). Cyclization of the intermediate using sodium methoxide (Dieckmann conditions) followed by hydrolysis and decarboxylation gives tetrabenazine (1) which is recrystallized from di-isopropyl ether.


Scheme 1: Method embodied in US 2,830,993 for preparation of tetrabenazine

The present inventors, while trying to replicate the synthetic method as disclosed in US 2,830,993 came across various difficulties as listed below.
a) During the synthesis of intermediate P-2, impurity-1 (structure given below) was invariably formed to a considerable extent of around 10%. Use of organic bases like dimethylaminopyridine (DMAP), triethylamine, diisopropylamine, and imidazole was not helpful. The impurity formation had to be controlled using inorganic bases like carbonates and water-hydrocarbon solvent systems.

b) For the conversion of P-2 to P-3, use of hygroscopic reagents like zinc chloride or phosphorous pentoxide proved to be extremely problematic in large scale operations. The hygroscopic reagents had to be replaced by phosphorous oxychloride (POCl3). However, when the reaction mixture was neutralized using bicarbonate, an undesired compound, labeled as impurity-2 (structure given below) was obtained. The inventors then concentrated the POCl3 reaction mixture as such, treated with borohydride and obtained the requisite compound.

c) Reaction of intermediate P-4 to give P-6 was associated with very poor conversion and yield. Further, attempts to improve the yield by changing and /or optimizing the experimental conditions as reported in US 2,830,993 were not quite successful. Thus, in addition to other difficulties, the overall yield remained too moderate, making the process unviable based on economic and practical considerations.
GB999095 discloses a different approach for synthesis of the tricyclic compound tetrabenazine wherein a 3,4-dihydro-isoquinoline derivative is condensed with a substituted ß-amino ketone or a salt thereof. The process comprises reaction of 6, 7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in alcohol as solvent at reflux temperature to give tetrabenazine (1).

Scheme 2: Method embodied in GB999095 for preparation of Tetrabenazine

WO2012081031A1 discloses a similar process wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline is treated with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide to give crude tetrabenazine. According to the invention, further purification by recrystallization in methanol provides crystalline form A of the pure compound.
IN 4923/CHE/2012 discloses a process wherein the intermediate, 3-dimethyl aminomethyl-5-methylhexan-2-one methiodide is purified by recrystallization in aqueous alcohol. Tetrabenazine is then obtained by reacting the purified intermediate with 6,7-dimethoxy-3,4-dihydroisoquinoline in presence of a phase transfer catalyst such as tetrabutylammonium bromide.
The above prior art methods involve use of amino ketone intermediate, 3-dimethylaminomethyl-5-methylhexan-2-one wherein the free base is converted to the corresponding methyl iodide salt for ease of isolation, purification and further use. However, this synthetic approach is also associated with several drawbacks and shortcomings as listed below.
i) Methyl iodide is a known mutagen. It also exhibits moderate to high acute toxicity for inhalation and ingestion and hence needs to be controlled below ppm levels. Further, since it is used at the penultimate stage in the synthesis of tetrabenazine, there are high chances of contamination of the finished product with mutagenic impurities.
ii) The stringent requirements of controlling methyl iodide levels below ppm limits necessitate extensive purification processes and the requisite analytical testing methods which, if followed, would cause a considerable rise in the project-cost. Exposure of the manufacturing personnel to genotoxic substances is a still bigger concern.
iii) Further, methyl iodide is a low boiling (boiling point 42.40C), dense, colorless, volatile liquid, which undergoes degradation when exposed to light. These properties make handling of the chemical very difficult, especially on a commercial scale.
iv) High cost of the reagent methyl iodide, which substantially contributes to the costing of the project, is also a deterrent to its use in commercial processes.
v) It was experimentally observed by the present inventors that when 3-dimethylaminomethyl-5-methylhexan-2-one methiodide was prepared as reported in prior art processes; it showed considerable coloration on storage.

Thus, in addition to significant contribution to API cost, use of methyl iodide poses several difficulties ranging from handling problems to mutagenic impurities.

Molecular Crystals and Liquid Crystals, 557(1), (2012) Pages 39-49, pp.41, discloses reaction of 3-dimethylaminomethyl-5-methylhexan-2-one free base with 6, 7-dimethoxy-3, 4-dihydroisoquinoline. The reaction requires use of a phase transfer catalyst like triethylbenzylammonium chloride at reflux temperature and provides tetrabenazine in moderate yield of 56%.
Hence, there still exists a need for an economical, industrially viable process for synthesis of tetrabenazine (1), which avoids use of genotoxic reagents and circumvents lengthy, elaborate purification processes for the intermediates and finished product.

The present inventors have developed a convenient, easy to scale up process for tetrabenazine (1), comprising use of acid addition salt of 3-(dimethylamino)methyl-5-methylhexan-2-one in presence of organic acid for the reaction with dihydroisoquinoline derivative. By following this process, the desired product, tetrabenazine, conforming to regulatory specifications, was obtained in good yield. Further, the process could easily be scaled up to a commercial level of manufacturing.

OBJECT OF THE INVENTION

An objective of the present invention is to provide tetrabenazine of formula (1) having desired purity by an industrially viable, convenient process which does not involve mutagenic reagents or cumbersome purification procedures for removal of impurities.

Yet another object of the present invention is to provide an efficient, cost-effective process for preparation of tetrabenazine (1) having desired purity, with a significant control on formation of impurities.

SUMMARY OF THE INVENTION

The present invention relates to a novel method for synthesis of tetrabenazine (1) having desired purity.

An aspect of the invention relates to a process for preparation of tetrabenazine (1) comprising reaction of 3-(dimethylamino)methyl-5-methylhexan-2-one (3) with an acid (A-H) in solvent-A to provide 3-(dimethylamino)methyl-5-methylhexan-2-one acid addition salt of formula (4), which on reaction with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7) in solvent-B and in presence of an organic acid provides tetrabenazine.

The objectives of the present invention will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors, while developing a convenient and industrially applicable synthetic method for tetrabenazine, aimed at a process which was free from mutagenic reagents and the associated genotoxic impurities. Further, the process needed to provide the final compound having desired purity in good yield, yet avoiding the cumbersome separation procedures to get rid of the associated impurities generated during the synthetic sequence.

It was observed that in some of the prior art methods tetrabenazine was prepared by following a lengthy, low-yielding, high cost process comprising preparation and cyclization of 1-carbethoxymethyl-2-(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (P-6 in scheme-1). The other methods resorted to use of the known mutagen, methyl iodide as a counter ion for the amine intermediate, 3-dimethylaminomethyl-5-methylhexan-2-one. The methyl iodide salt, although provided for ease of handling and purification prior to further use, imposed stringent requirement of controlling its contamination to ppm level.

It may be noted that during the synthesis of 3-dimethylaminomethyl-5-methylhexan-2-one from 5-methyl-2-hexanone and dimethylamine hydrochloride, the desired ketone being a liquid, poses difficulties during isolation and purification procedures. The purification methods involving techniques such as chromatographic separation, distillation etc. are time consuming and are likely to incur loss in yield.

The inventors then tried converting 3-dimethylaminomethyl-5-methylhexan-2-one to different acid addition salts for reaction with 6,7-dimethoxy-3,4-dihydroisoquinoline to provide tetrabenazine. Various inorganic and organic acids, referred to as (A-H), selected from hydrochloric acid, sulfuric acid, acetic acid, tartaric acid, succinic acid, malic acid, maleic acid, oxalic acid etc. were used for the said reaction. Optically active organic acids such as dibenzoyl-D-tartaric acid, di-p-anisoyl-D-tartaric acid, O,O’-di-p-toluoyl-D-tartaric acid were also used in the preparation of the said salts.

It was observed that while some of the acids tried by the inventors provided the corresponding salts in moderate yield as oily, viscous compounds which were difficult to isolate, some salts such as oxalate were formed in good to almost quantitative yield and could easily be isolated as free flowing solids having desired purity. These acid-addition salts, wherein the counter-ion originated from the acid and has been denoted by A, were then used in preparation of tetrabenazine. Free-flowing solids like oxalate salts were found to be easy to handle as compared to other oily, viscous salts, which posed difficulties in isolation and use in further reactions.

The acid addition salts were directly subjected to the reaction with 6, 7-dimethoxy-3, 4-dihydroisoquinoline to provide tetrabenazine. It was surprisingly found that due to the presence of acid in the salt, the dimethyl amine group was protonated throughout the reaction, making it a better leaving group. This ensured faster reaction as well as complete conversion.
The use of oxalic acid and similar organic acids for salt formation proved beneficial in multiple ways.
i) The acids being non-mutagenic, cost-effective, readily available, easy to handle
chemicals, were reagents of choice for preparation of the amine salt.
ii) The process not only avoided expensive mutagenic reagents like methyl iodide and the consequential exposure of the production personnel, but also circumvented formation of genotoxic impurities and subsequent purification and analytical procedures.
iii) As against the experimentally observed moderate yield of 70-78% for the methyl iodide salt, the organic acid salts were obtained in good to near-quantitative yields, which significantly improved the overall yield for tetrabenazine, providing a cost-effective process.

While carrying out the reaction of acid addition salt of 3-dimethylaminomethyl-5-methylhexan-2-one with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride, the present inventors serendipitously observed that when the reaction was carried out in presence of an organic acid, which probably enhanced the afore-mentioned protonation, the reaction was facile, faster, proceeded with good conversion and provided tetrabenazine having desired purity in good yield. It was further observed that the desired effects were observed even when the organic acid was used in catalytic quantities.
In the absence of the organic acid, the conversion was slow and incomplete which not only increased the batch time but also required prolonged heating, causing a substantial increase in impurity formation. Formation of impurities lowered the yield, and caused an increase in the project cost.

Thus, the present synthetic strategy effectively replaces the mutagenic reagents in prior art processes and provides an industrially feasible, economical, convenient process for tetrabenazine, wherein the final product is obtained in good overall yield and possesses purity conforming to specifications.

Scheme 1: Method embodied in present invention for preparation of tetrabenazine (1)

In an embodiment, 5-methyl-2-hexanone (2) is treated with dimethylamine hydrochloride and paraformaldehyde in an organic solvent to give 3- (dimethylamino)methyl-5-methylhexan-2-one (3), along with the undesired isomeric impurity (3a).
The organic solvent is selected from the group of alcohols such as ethanol, methanol, isopropyl alcohol etc. and mixtures thereof. The reaction is carried out in the temperature range of 60-850C.
After completion of reaction as monitored by GC, the reaction mass is concentrated, diluted with water, with an optional washing using hydrocarbon like cyclohexane. The mixture is basified using sodium hydroxide and extracted with ethyl acetate. Addition of para-toluene sulfonic acid to remove the undesired isomeric impurity, filtration and concentration of the filtrate provides the desired compound (3).

In another embodiment, compound (3) is treated with an acid (A-H) selected from the group of acetic acid, tartaric acid, succinic acid, malic acid, malonic acid, maleic acid, oxalic acid dibenzoyl-D-tartaric acid, camphor sulfonic acid, di-p-anisoyl-D-tartaric acid, O,O’-di-p-toluoyl-D-tartaric acid etc., preferably oxalic acid, in an organic solvent to give the corresponding acid addition salt. The reaction is carried out in the temperature range of 20-40°C.
The organic solvent is selected from the group of ketones such as methyl isobutyl ketone, acetone, methyl ethyl ketone, cyclohexanone, methyl amyl ketone etc., alcohols such as methanol, ethanol, isopropanol, isobutanol etc., esters like methyl acetate, ethyl acetate, butyl acetate etc. and mixtures thereof. The ketone solvents such as acetone are preferred. For the sake of convenience, these solvents are referred to as solvent-A.

In another embodiment, compound (3) is treated with an acid selected from hydrochloric acid and sulfuric acid in an organic solvent (Solvent-A) to give the corresponding acid addition salt. The reaction is carried out in the temperature range of 20-40°C.

After completion of the salt formation reaction, as monitored by GC, the acid addition salt, wherein the counter-ion, originating from acid is denoted as A, is separated employing techniques like precipitation, solvent extraction, crystallization, filtration etc. depending upon the nature of the salt in the reaction mass. Precipitation, solvent extraction, liquid-liquid phase separation type techniques are used for separating the oily, viscous salts whereas filtration, crystallization procedures are carried out for solid salts.
For example, the oxalate salt (4-a) is obtained as a stable solid which is filtered and dried.
In yet another embodiment, 3,4-dimethoxyphenylethylamine (5), also known as homoveratryl amine is treated with formic acid in an organic solvent to give n-formyl-3,4-dimethoxyphenylethylamine (6). The organic solvent is selected from the group of aprotic solvents such as acetonitrile, tetrahydrofuran etc.; hydrocarbon solvents such as toluene, xylene etc.; and mixtures thereof. Optionally, a ‘neat’ reaction, wherein no solvent is used, is done to provide the desired compound (6).

The reaction is carried out in the temperature range of 50°C to 85°C, preferably at reflux temperature of the solvent.
After completion of the reaction, as monitored by HPLC, the reaction mass is concentrated to provide the desired formyl derivative (6) which is then further treated with phosphorous oxychloride in acetonitrile as solvent at 20-45°C to provide the cyclized compound, 6,7-dimethoxy-3,4-dihydroisoquinoline as a free base. After completion of the reaction, as monitored by HPLC, the reaction mass is concentrated, basified using sodium hydroxide and extracted with ethyl acetate. Further treatment of the separated organic layer with anhydrous hydrogen chloride in ethyl acetate in the temperature range of 5°C to 35°C, followed by filtration provided 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (7).
In a further embodiment, the compound of formula (4), which is an acid addition salt of 3-(dimethylamino) methyl-5-methylhexan-2-one (3) is reacted with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7) in a solvent. The reaction is carried out in the temperature range of 450C to 900C, in presence of an organic acid which may be used in catalytic quantities.

The solvent is selected from water, alcohols such as ethanol, methanol, isopropyl alcohol etc., and mixtures thereof. For the sake of convenience, the above-mentioned solvents are referred to as solvent-B.

Mixture of isopropyl alcohol and water employed for the reaction was in the range of 30:70 (v/v) to 70:30 (v/v).

The organic acid is selected from substituted and unsubstituted benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, para-toluene sulfonic acid, citric acid and acetic acid. The substituted benzoic acid is selected from ortho, meta, para-toluic acid, ortho, meta, para ethyl benzoic acid, and ortho, meta, para nitro benzoic acid.

After completion of the reaction, as monitored by HPLC, the reaction mass is concentrated, basified using sodium hydroxide and extracted with a halogenated hydrocarbon solvent selected from dichloromethane, ethylene chloride, chloroform etc. Separation and concentration of the separated organic layer gave a residue containing tetrabenazine which was optionally treated with isopropyl alcohol for further purification.
The reaction was carried out with any of the acid addition salts of compound (3) such as oxalate (4a), hydrochloride (4b), sulfate (4c), acetate (4d), tartrate (4e), succinate (4f), malate (4g), malonate (4h) maleate (4i), dibenzoyl-D-tartrate (4j), camphor sulfonate (4k), di-p-anisoyl-D-tartrate (4l), O,O’-di-p-toluoyl-D-tartrate (4m) etc. The oxalate salt (4-a) obtained as a free flowing solid was employed for the reaction.
After completion of reaction as monitored by HPLC, the reaction mass was concentrated, and treated with an aqueous alkali solution such as sodium hydroxide and extracted with halogenated hydrocarbon solvent selected from dichloromethane, ethylene chloride, chloroform etc. Separation and concentration of the separated organic layer provided a residue containing tetrabenazine which is optionally treated with isopropyl alcohol for further purification.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one (3)
Paraformaldehyde (255.2 g) was added to the mixture of dimethylamine hydrochloride (580.0 g) in methanol (2320 ml), stirred at 200C-400C, followed by gradual addition of 5-methyl-2-hexanone (2, 1220.3 g). The reaction mixture was stirred at 750C to 800C till completion of the reaction as monitored by GC.
After completion, the reaction mixture was concentrated and water was added to the residue, followed by an optional washing with cyclohexane. The resulting mixture was basified using aqueous sodium hydroxide solution and extracted with ethyl acetate, followed by separation and concentration of the organic layer.
Ethyl acetate was added to the residue, followed by addition of p-toluenesulfonic acid (580 g) and stirred till completion of the reaction as monitored by GC. The precipitated solid was filtered and the filtrate was washed with water and dilute alkali solution. Separation and concentration of the organic layer provided 3- (dimethylamino)methyl-5-methylhexan-2-one.
Yield: 668 g (55 %), Purity: > 98.5% (GC)
1H NMR (DMSO-D6, 400 MHz) d (ppm): 0.83 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 1.12-1.18 (m, 1H), 1.36-1.44 (m, 2H), 2.04-2.10 (m, 10H), 2.48-2.54 (m, 1H), 2.65-2.71 (m, 1H).
13C NMR: (DMSO-D6, 100 MHz, d (ppm): 21.98, 22.88, 25.65, 27.70, 38.54, 45.26, 48.97, 61.76, 211.11, Mass: 172.1 (M+H).

Example 2: Preparation of acid addition salt of 3-(dimethylamino)methyl-5-methylhexan-2-one
General procedure: 3-(dimethylamino)methyl-5-methylhexan-2-one (3) was stirred in five to ten volumes of solvent and treated with one to two equivalents of acid at 200C to 400C. The reaction was continued till completion of the salt formation, as monitored by GC.
The solvent was selected from methyl isobutyl ketone, acetone, methyl ethyl ketone, cyclohexanone, methyl amyl ketone, methanol, ethanol, isopropanol, isobutanol, methyl acetate, ethyl acetate, butyl acetate and mixtures thereof.
Amongst the solvents, acetone was preferably used.
After completion of the reaction, the acid addition salt was isolated from the reaction mass employing techniques like solvent concentration, precipitation, solvent extraction, crystallization, filtration etc. depending upon the nature of salt. For separating the oily, pasty, viscous salts, techniques like precipitation using a solvent such as methyl tertiary butyl ether, or solvent extraction, liquid-liquid phase separation were used, whereas filtration, crystallization procedures were employed for separation of solid acid addition compounds.

Example 2a: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one oxalate (4a)
Oxalic acid dihydrate (220.76 g) was added to a stirred solution of 3-(dimethylamino)methyl-5-methylhexan-2-one (3, 300 g) in acetone (1500 ml) at 20-400C, and the mixture was stirred at the same temperature till completion of the reaction as monitored by GC. After completion, the resulting solid was filtered and dried under vacuum to give the oxalate salt of 3-(dimethylamino)methyl-5-methylhexan-2-one (4a).
Yield: 412.7 g (90%), Purity: 98.5% (GC)
1H NMR (DMSO-D6, 400 MHz) d (ppm): 0.88 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 1.14-1.21 (m, 1H), 1.37-1.44 (m, 1H), 1.49-1.58 (m, 1H), 2.19 (S, 3H), 2.61 (S, 6H), 2.84 (dd, J = 3.2, 12.8 Hz, 1H), 2.98-3.04 (m, 1H), 3.27 (dd, J = 9.2, 12.8 Hz, 1H), 11.57 (br. s, 2H), 13C NMR: (DMSO-D6, 100 MHz) d (ppm): 22.09, 22.45, 25.23, 28.39, 38.53, 43.16, 46.04, 57.05, 164.28, 209.27, Mass: 172.1 (M+1).
Elemental analysis (C12H23NO5): C, 55.10, H, 8.08, N, 5.35, O, 30.61, Observed: C, 55.26, H, 8.67, N, 5.34.

Example 2b: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one hydrochloride (4b)
The hydrochloride salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino)methyl-5-methylhexan-2-one hydrochloride (4b)
1H NMR (DMSO-D6, 400 MHz) d(ppm) : 0.86 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 1.18-1.25 (m, 1H), 1.34-1.41 (m, 1H), 1.52-1.60 (m, 1H), 2.62 (d, J = 4.8 Hz, 3H), 2.68 (d, J = 5.2 Hz, 3H), 2.96-3.01 (m, 1H), 3.07-3.14 (m, 1H), 3.37-3.44 (m, 1H), 7.35 (s, 1H); 13C NMR (DMSO-D6, 100 MHz) d(ppm) : 22.12, 22.51, 25.16, 28.84, 38.67, 42.54, 42.69, 45.57, 56.01, 208.85; Mass: 172.1 (M+1).

Example 2c: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one tartrate (4e)
The tartrate salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino)methyl-5-methylhexan-2-one tartrate (4e)
1H NMR (DMSO-D6, 400 MHz) d(ppm) : 0.81 (d, 3H, J = 7.92 Hz), 0.84 (d, 3H, J = 6.4 Hz), 1.13-1.16 (m, 1H), 1.35-1.45 (m, 2H), 2.06 (s, 2H), 2.15 (s, 6H, contains 4-OH and –CH2), 2.51 (s, 6H), 2.56-2.62 (m, 1H), 2.69-2.71 (m, 2H), 3.98 (s, 2H).

Example 2d: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one malonate (4h)
The malonate salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino)methyl-5-methylhexan-2-one malonate (4h)

1H NMR (DMSO-D6, 400 MHz) d(ppm): 0.86 (d, 3H, J = 4.72 Hz), 0.88 (d, 3H, J = 4.68 Hz), 1.14-1.21 (m, 1H), 1.39-1.48 (m, 1H), 1.5-1.55 (m, 1H), 2.16 (s, 3H), 2.49-2.56 (m, 8H), 2.66-2.71(m, 1H), 2.89-2.92 (m, 2H), 3.07-3.10 (m, 1H).

Example 2e: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one dibenzoyl-D-tartrate (4j)
The dibenzoyl-D-tartrate salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino) methyl-5-methylhexan-2-one dibenzoyl-D-tartrate (4j)
1H NMR (CDCl3, 400 MHz) d : 0.79-0.85 (m, 6H), 1.06-1.33 (m, 1H), 1.25-1.32 (m, 1H), 1.47-1.53 (m, 1H), 2.13 (d, J = 6.16 Hz, 3H), 2.61 (d, J = 3.96 Hz, 6H), 2.78-2.85 (m, 1H), 3.14-3.18 (m, 1H), 3.36-3.43 (m, 1H), 5.80 (s, 2H), 7.36 (m, 4H), 7.38-7.51 (m, 2H), 8.05-8.08 (m, 4H)

Example 2f: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one camphor sulfonate (4k)
The camphor sulfonate salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino)methyl-5-methylhexan-2-one camphor sulfonate (4k)
1H NMR (DMSO-D6, 400 MHz) d(ppm) 0.74 (s, 3H), 0.89 (d, 3H, J = 6.56 Hz), 0.92 (d, 3H, J = 6.52Hz), 1.04 (s, 3H), 1.05-1.28 (m, 3 H), 1.39-1.49 (m, 2H), 1.54-1.59 (m, 1H), 1.76-1.86 (m, 2H), 1.93 (t, 1H, J = 4.56 Hz), 2.21-2.29 (m, 4H), 2.36 (d, 1H, J = 14.68 Hz), 2.69-2.75 (m, 6H), 2.86 (d, 1H, 14.68 Hz), 2.96-3.03 (m, 2H), 3.35-3.38 (m, 1H), 9.05 (s, 1H, exchangeable)

Example 2g: Preparation of 3-(dimethylamino)methyl-5-methylhexan-2-one di-p-anisoyl -D-tartrate (4l)
The di-p-anisoyl-D-tartrate salt was prepared by following the aforementioned general procedure.
Spectral data for 3-(dimethylamino)methyl-5-methylhexan-2-one di-p-anisoyl -D-tartrate (4l)
1H NMR (CDCl3, 400 MHz) d: 0.82-0.87 (m, 6H), 1.07-1.14 (m, 1H), 1.25-1.33 (m, 1H), 1.49-1.54 (m, 1H), 2.16 (d, 3H, J = 12.28 Hz), 2.6 (d, J = 3.48 Hz, 6H), 2.76-2.82 (m, 1H), 3.14-3.18 (m, 1H), 3.35-3.42 (m, 1H), 3.82 (s, 6H), 5.77 (s, 2H), 6.82-6.86 (m, 4H), 7.99-8.02 (m, 4H).

Example 3: Preparation of 6,7-dimethoxy-3,4–dihydroisoquinoline hydrochloride (7)
Formic acid (27.9 g) was added to a solution of 3,4-dimethoxyphenylethylamine (5) (100g) in acetonitrile (400 ml) and the reaction was continued at reflux temperature till completion of the reaction as monitored by HPLC. After completion, the reaction mass was concentrated to give compound (6) as an oily residue, which was used for further reaction.
Phosphorous oxychloride (93.1 g) was gradually added to the mixture of above residue in acetonitrile (400 ml) and the reaction mixture was stirred at 40°C to 45 °C till completion of the reaction as monitored by HPLC. After completion, the reaction mass was concentrated, basified using aqueous sodium hydroxide solution till a pH between 9 and 10 was attained. Extraction with ethyl acetate, followed by separation and concentration of the organic layer provided a residue containing 6,7-dimethoxy-3,4–dihydroisoquinoline free base.
Anhydrous hydrogen chloride in ethyl acetate (8-10%, 200 ml) was gradually added to mixture of the residue in ethyl acetate, cooled at 5°C to 10 °C. The reaction mass was stirred at 25°C to 30 °C till completion of the hydrochloride salt formation as monitored by TLC, HPLC. The resulting solid was filtered to give compound (7) as a light yellow solid.
Yield: 106.3 g, (85 %), Purity: >98.5 % (HPLC)
1H NMR (DMSO-D6, 400 MHz) d(ppm) : 3.07 (t, 2H, J = 8.4 Hz), 3.75 (s, 3H), 3.80-3.87 (m, 2H), 3.92 (s, 3H), 7.16 (s, 1H), 7.53 (s, 1H), 8.95 (s, 1H), 13C NMR (DMSO-D6, 100 MHz) d(ppm): (23.78, 40.72, 56.05, 56.55, 111.68, 115.58, 116.72, 133.67, 148.02, 156.66, 164.34, Mass: 192.1.

Example 4: Preparation of 6,7-dimethoxy-3,4–dihydroisoquinoline hydrochloride (7)
3,4-dimethoxyphenylethylamine (5) (25.2 g) was converted to 6,7-dimethoxy-3,4–dihydroisoquinoline free base following the procedure in example 3.
Isopropanol (150 ml) was added to the residue containing the free base, followed by gradual addition of aqueous hydrochloric acid till a pH between 1 and 2 was attained. Stirring was continued at 25°C to 30 °C till completion of the hydrochloride salt formation as monitored by TLC, HPLC. The stirred reaction mass was cooled to 10 °C to 15°C and filtered to provide 6,7-dimethoxy-3,4–dihydroisoquinoline hydrochloride (7).
Yield: 22.5 g (72 %), Purity: 95 % (HPLC)

Example 5: Preparation of Tetrabenazine (1)
Compound 4a, 3-(dimethylamino)methyl-5-methylhexan-2-one oxalate (72.6 g) was added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 55.0 g) in a mixture of IPA and water (3:5, 440 ml). The reaction mixture was stirred at 75°C to 80 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 41.0 g (53.6%), Purity: 96.6% (HPLC)
1H NMR (CDCl3, 400 MHz) d(ppm) : 0.91 (d, 3H, J = 6.52 Hz), 0.92 (d, 3H, J = 6.4 Hz), 1.01-1.06 (m, 1H), 1.60-1.69 (m, 1H), 1.77-1.84 (m, 1H), 2.35 (t, 1H, 11.6 Hz), 2.50-2.62 (m, 2H), 2.72-2.76 (m, 2H), 2.9 (dd, 1H, J = 3.04, 13.56 Hz), 3.07-3.16 (m, 2H), 3.29 (dd, 1H, J = 6.28, 11.56 Hz), 3.5 (d, 1H, J = 11.96 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 6.55 (s, 1H), 6.61 (s, 1H).
Mass: 318.44 (M+1).

Example 6: Preparation of Tetrabenazine (1)
Compound 4a, 3-(dimethylamino)methyl-5-methylhexan-2-one oxalate (145.2 g,) and benzoic acid (8.84 g) were added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 110.0 g) in a mixture of IPA and water (3:5, 880 ml). The reaction mixture was stirred at 75°C to 80 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 99.5 g (65%), Purity: 99.87% (HPLC)
1H NMR (CDCl3, 400 MHz) d(ppm) : 0.91 (d, 3H, J = 6.52 Hz), 0.92 (d, 3H, J = 6.4 Hz), 1.01-1.06 (m, 1H), 1.60-1.69 (m, 1H), 1.77-1.84 (m, 1H), 2.35 (t, 1H, 11.6 Hz), 2.50-2.62 (m, 2H), 2.72-2.76 (m, 2H), 2.9 (dd, 1H, J = 3.04, 13.56 Hz), 3.07-3.16 (m, 2H), 3.29 (dd, 1H, J = 6.28, 11.56 Hz), 3.5 (d, 1H, J = 11.96 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 6.55 (s, 1H), 6.61 (s, 1H).
Mass: 318.44 (M+1).

Example 7: Preparation of Tetrabenazine (1)
Compound 4e, 3-(dimethylamino)methyl-5-methylhexan-2-one tartrate (77.6 g,) and benzoic acid (2.95 g) were added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 36.7 g) in a mixture of IPA and water (3:5, 330 ml). The reaction mixture was stirred at 65°C to 85 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 29.6 g (58%), Purity: 99.67% (HPLC)

Example 8: Preparation of Tetrabenazine (1)
Compound 4b, 3-(dimethylamino)methyl-5-methylhexan-2-one hydrochloride (65.4 g,) and benzoic acid (3.84 g) were added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 47.8 g) in a mixture of IPA and water (3:5, 385 ml). The reaction mixture was stirred at 70°C to 85 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 39.5 g (59.3%), Purity: 99.17% (HPLC)

Example 9: Preparation of Tetrabenazine (1)
Compound 4h, 3-(dimethylamino)methyl-5-methylhexan-2-one malonate (66.0 g) and benzoic acid (2.95 g) were added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 36.7g) in a mixture of IPA and water (3:5, 330 ml). The reaction mixture was stirred at 65°C to 85 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 28.1 g (55.0%), Purity: 99.17% (HPLC)

Example 10: Preparation of Tetrabenazine (1)
Compound 4k, 3-(dimethylamino)methyl-5-methylhexan-2-one camphor sulfonate (72.5 g,) and benzoic acid (2.20 g) were added to the stirred solution of 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7, 27.3g) in a mixture of IPA and water (3:5, 245 ml). The reaction mixture was stirred at 70°C to 90 °C till completion as monitored by HPLC. After completion, the reaction mass was concentrated and aqueous sodium hydroxide solution was added to the residue. Extraction of the resulting mixture with dichloromethane, followed by separation and concentration of the organic layer gave tetrabenazine (1) which was optionally purified using isopropyl alcohol.
Yield: 19.5 g (51.3%), Purity: 98.3% (HPLC).

,CLAIMS: We Claim,

1. A process for the preparation of tetrabenazine (1), comprising reaction of 3- (dimethylamino)methyl-5-methylhexan-2-one (3) with an acid (A-H) in presence of solvent-A to provide 3-(dimethylamino)methyl-5-methylhexan-2-one acid addition salt of formula (4), followed by reaction with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7) in presence of solvent-B and an organic acid to give tetrabenazine.

2. A process for the preparation of tetrabenazine (1), comprising reaction of 3- (dimethylamino)methyl-5-methylhexan-2-one acid addition salt of formula (4), with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7) in presence of solvent-B and an organic acid to give tetrabenazine.

3. The process as claimed in claims 1 and 2, wherein the acid (A-H) for preparation of acid addition salt of formula (4) is selected from hydrochloric acid, sulfuric acid , acetic acid, tartaric acid, succinic acid, malic acid, malonic acid, maleic acid, oxalic acid, dibenzoyl-D-tartaric acid, camphor sulfonic acid, di-p-anisoyl-D-tartaric acid, and O,O’-di-p-toluoyl-D-tartaric acid.
4. The process as claimed in claims 1 and 2, wherein the organic acid is selected from benzoic acid, ortho, meta, para toluic acid, ortho, meta, para ethyl benzoic acid, and ortho, meta, para nitro benzoic acid.
5. The process as claimed in claim 1, wherein solvent-A is selected from the group of ketones selected from methyl isobutyl ketone, acetone, methyl ethyl ketone, cyclohexanone, methyl amyl ketone, the group of alcohols selected from methanol, ethanol, isopropanol, isobutanol, and the group of esters selected from methyl acetate, ethyl acetate, butyl acetate and mixtures thereof.
6. The process as claimed in claims 1 and 2, wherein solvent-B is selected from water, alcohol selected from group of ethanol, methanol, isopropanol and mixtures thereof.
7. The process as claimed in claims 1 and 2, wherein the temperature is between 450C and 900C.
8. The process as claimed in claims 1, 2 and 7, wherein the temperature is between 700C and 900C.
9. The process as claimed in claims 1 and 2, wherein 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (7) is obtained by reaction of 3,4-dimethoxyphenylethylamine (5) with formic acid in acetonitrile as solvent, followed by treatment of the resulting n-formyl-3,4-dimethoxyphenylethylamine (6) with phosphorous oxychloride to furnish 6, 7-dimethoxy-3, 4-dihydroisoquinoline, followed by reaction with hydrogen chloride in ethyl acetate to give compound (7).
10. A process for the preparation of tetrabenazine (1), comprising the reaction of 3-(dimethylamino)methyl-5-methylhexan-2-one oxalate (4a) with 6,7-dimethoxy-3,4-dihydroisiquinoline hydrochloride (7) at 700C to 900C in presence of benzoic acid using isopropyl alcohol and water as solvent.