This application claims priority to this Indian patent application number 4923/CHE/2012 filed on Nov 26, 2012.

FIELD OF THE INVENTION:

The present disclosure relates to process for the purification of a tetrabenazine intermediate to remove specific impurities. The intermediate can be converted to tetrabenazine with improved yield and quality.

BACKGROUND:

Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder. United States Food and Drug Administration (USFDA) approved tetrabenazine to treat chorea associated with Huntington's disease (HD).

Tetrabenazine is chemically known as cis rac-1,3,4,6,7,11 b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.represented by compound of formula (I).
h,3C0>YVNl H3CO^^VN-| CH3
(I)

U.S. Pat. No. 2830993 discloses a process for the preparation of tetrabenazine (I) wherein 1-carbethoxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (III) is reacted with mono-isobutylmalonic acid dimethyl ester (X) and paraformaldehyde in methanol solvent to produce 1-carbethoxymethyl-2 (2, 2-dicarbomethoxy-4-methyl-n-pentyl)-6, 7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (II), which is then subjectedto Dieckmann cyclization , followed by hydrolysis and decarboxylation, to form tetrabenazine (the compound of formula (I)), which is then recrystallized from di-isopropyl ether. This stepwise process is shown in Scheme-I.

Scheme-I
GB999095 discloses a process for the preparation of tetrabenazine ((I)) wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline-hydrochIoride (IV) is reacted with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (IX) in alcohol solvent at reflux temperature to give tetrabenazine (I). The stepwise process is as shown in Scheme-ll.

International Publication No. WO2012081031A1 discloses a process for the preparation of tetrabenazine of formula (I) wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline (compound of formula (V)) is reacted with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (IX) to get crude tetrabenazine The crude tetrabenazine is purified by recrystallizing with methanol. This stepwise process is shown in Scheme-IV

Scheme-IV
3-dimethylaminomethyl-5-methylhexan-2-one methiodide of formula (IX) prepared by prior art processes leads to the formation of impurities. Therefore there is a need in the art to develop an improved purification process for 3-dimethylaminomethyl-5-methylhexan-2-one methiodide.

Processes for purification of3-dimethylaminomethyl-5-methylhexan-2-one methiodide(IX) that control or reduct impurities are not disclosed in the prior art. The present invention provides an improved process for the purification of 3-dimethylaminomethyl-5-methylhexan-2-one methiodide intermediate which can be further converted to tetrabenazine with improved yield and quality.

SUMMARY:

A first aspect of the disclosure is to provide a process for purification of 3-dimethylaminomethyl-5-methylhexan-2-one methiodide of formula (IX), which can be converted tetrabenazine.

In one aspect, the process for purification of intermediate of formula (IX) comprises the steps of:
a) suspending 3-dimethylaminomethyl-5-methyihexan-2-one methiodide in a mixture of water and water miscible solvent,

b) heating the mixture to get a clear solution,

c) cooling the clear solution to room temperature, and

d) isolating pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide from the solution.

Still another aspect is to provide substantially pure tetrabenazine having less than 0.05% (wt%?) of the compounds of formulae (X), (XI), (XII), (XIII) and (XIV).

Yet another aspect relates to a process for the preparation of substantially pure tetrabenazine comprising the steps of;

a) reacting homoveratrylamine with ethyl formate to form N-(3,4-dimethoxy phenethyl-acetamide,

b) reacting the N-(3,4-dimethoxy phenethyl- acetamide obtained in step a) with phosphorus oxychloride to form 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride trihydrate,

c) reacting 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride trihydrate obtained in step b) with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in water in the presence of phase transfer catalyst to yield tetrabenazine,

d) optionally purifying the tetrabenazine obtained in step c), and

e) isolating pure tetrabenazine

The step wise process of present invention is shown in scheme-V.

Yet another aspect is to provide a novel compound of formula (XI)

DETAILED DESCRIPTION:

The present disclosure relates to a purification of a tetrabenazine intermediate to remove specific impurities. The intermediate is then converted to tetrabenazine with improved yield and quality.
One embodiment of the disclosure is to provide substantially pure tetrabenazine.
Another embodiment relates to a process for purification of 3-dimethylaminomethyl-5-methylhexan-2-one methiodide comprising the steps of:

a) suspending 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in a mixture of water and water miscible solvent,

b) heating the mixture to get a clear solution,

c) cooling the solution to room temperature, and

d) isolating pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide from the solution.

The crude 3-dimethylaminomethyl-5-methylhexan-2-one methiodide of formula (IX) is taken up in 5% aqueous alcohol, heated to 60°-65°C to get clear solution is stirred for 30 min. The mass is cooled to 25°-30°C, stirred for 4 hrs and the obtained solid is filtered to get pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide.

Yet another embodiment relates to a process for purification of the compound of formula (IX), in which 3-dimethylaminomethyl-5-methylhexan-2-one is distilled under vacuum, followed by reaction with methyl iodide to get pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (IX).

According to the present disclosure, pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (IX) has less than 3% of the isomeric impurity of formula (XV)

Yet another embodiment relates to a process for the preparation of substantially pure tetrabenazine, the process comprising the steps of;

a) reacting homoveratrylamine with ethylformate to form N-(3,4-dimethoxy phenethyl)acetamide,

b) reacting N-(3,4-dimethoxy phenethyl)acetamide obtained in step a) with phosphorus oxychloride to form 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride trihydrate,

c) reacting 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride trihydrate obtained in step b) with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in water in the presence of phase transfer catalyst to yield tetrabenzine,

d) optionally purifying the obtained tetrabenazine in step c), and

e) isolating pure tetrabenazine.

The homoveratrylamine (formula (VII)) is reacted with ethylformate at 50°C to 55°C and maintained at same temperature for 4-6 hrs. After completion of the reaction, ethylformate is distilled off under vacuum to get a residue. Phosphorus oxychloride is added in the presence of acetonitrile at 10-20°C. The reaction mixture temperature is raised to 70 - 75°C and maintained for 4-6 hrs for completion of reaction;

acetonitrile is distilled off completely to get a residue, water is added and the pH is adjusted to 8-9 using 25% aqueous ammonia , followed by addition of a ester solvent to separate the layers. The organic layer is distilled off completely at 50-55°C, alcoholic solvent is added and pH is adjusted to 1-2 using aqueous hydrochloride. The mixture is stirred at ambient temperature and cooled to 10-15°C, and the resulting solid is filtered and washed with alcohol solvent to get 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride of formula (IV).

The compound of formula (IV) is dissolved in water and pH is adjusted to 8-9 using 20% aqueous potassium carbonate solution. The compound is extracted into chlorinated solvent, water is added, followed by 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (IX) and phase transfer catalyst the temperature of the mixture is raised to 93-98°C and maintained for 4- 6 hrs to complete the reaction. After completion of the reaction, temperature is cooled to 25-35°C. An ester solvent is added and stirred to filter the undissolved solid; water is added to the filtrate and separated the layers. The solvent is distilled off completely under vacuum at 40-60°C to get a residue. Alcohol solvent is added to residue, heated to 75-80°C and then cooled to 25-30°C. The obtained solid is filtered to get wet solid and recrystallized in alcohol solvent to obtain substantially pure tetrabenazine.

Examples of ester solvents that can be used include, but are not limited, to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate isopropyl acetate or mixtures thereof.

Preferred ester solvent is ethyl acetate, Exanmples of the chlorinated solvent include, but are not limited to, dichloromethane, dichloroethane, chloroform or mixtures thereof. Preferred chlorinated solvent is dichlormethane Examples of the alcohol solvent include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof. Preferred alcohol solvents are isopropyl alcohol, ethanol and methanol.

According to the present disclosure, the phase transfer catalyst may be but is not limited to tetrabutylammonium bromide (TBAB); tetrabutylammonium acetate; tetrabutylammonium hydrogensulphate; tetraethylammonium bromide; methyltributylammonium chloride (MTBAC); tetrabutylammonium hydroxide (TBAH); benzyltrimethylammonium hydroxide (BTMAH); tetramethylammonium hydroxide (TMAH); tributylbenzylammonium chloride and triethyl benzyl ammonium chloride ( TEBAC). Preferred phase transfer catalyst is triethyl benzyl ammonium chloride (TEBAC).

According to the present disclosure, tetrabenazine prepared from this embodiment having less than 0.05% of impurities, particularly less than 0.05% of impurities of the compounds of formulae (X), (XI), (XII), (XIII) and (XIV).

According to the present disclosure, the compound of formula (X) refers to 9, 10-dimethoxy-3-(2-methylpropyl)-3, 4, 6, 7-tetrahydro-2/-/-pyrido [2, 1-a] isoquinolin-2-one (or) dehydro impurity;

According to the present disclosure, the compound of formula (XI) refers to 9, 10-dimethoxy-2-(2-methylpropyl)-1, 6, 7, 11 b-tetrahydro-2/-/-pyrido [2, 1-a] isoquinolin-3(4/-/)-one (or) 3-keto impurity;
According to the present disclosure, the compound of formula (XII) refers to 3-butyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2/-/-pyrido[2,1-a]isoquinolin-2-one (or) n-butyl impurity ;

According to the present disclosure, the compound of formula (XIII) refers to (3S, 11bR)-3-isobutyl-9, 10-dimethoxy-3, 4, 6, 7-tetrahydro-1H-pyrido [2, 1-a] isoquinolin-2(11bH)-one (or) 3S-diastereomer impurity;

According to the present disclosure, the compound of formula (XIV) refers to (3R, 11bS)-3-isobutyl-9, 10-dimethoxy-3, 4, 6, 7-tetrahydro-1H-pyrido [2, 1-a] isoquinolin-2(11bH)-one (or) 3R-diastereomer impurity.
According to the present disclosure, the compound of formula (XV) refers to 1-(dimethylamino)-6-methyl heptanone (or) isomeric impurity.

Yet another embodiment is the compound of formula (XI)

According to the present disclosure, the table below shows typical tetrabenazine impurity limits for tetrabenzine prepared according to the present invention.

Yet another embodiment relates to a pharmaceutical composition comprising tetrabenazine prepared according to the present invention and a pharmaceutical^ acceptable carrier.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

Example-1
Preparation of 6, 7-dimethoxy-3, 4-dihydro isoquinoline hydrochloride trihydrate

Ethylformate (300 mL) was added to homoveratrylamine (100 gm) over a period of 60-90 min at about 25°-35°C, temperature was raised to about 50°-55°C and stirred for about 5 hours. After completion of reaction, the excess ethylformate was completely distilled under vacuum to gave residue of (6, 7-Dimethoxy phenyl) ethylformamidine. Acetonitrile (500 mL) was added to this residue, followed by slow addition of phosphorus oxychloride (60 mL) about 10°-20°C and maintain for about 6 hrs at about 70°-75°C. After completion the reaction, solvent was distilled off under vacuum up to residual volume of around 150 mL. The reaction mass was cooled to about 15°-20°C, followed by addition of water (300mL). pH of the solution was adjusted to 8-9 with aqueous ammonia solution. Ethyl acetate (500 mL) was added to the solution to separate, ethyl acetate layer was washed with water (100mL). The ethyl acetate layer was distilled under vacuum at below about 50°C to get a residue. Isopropyl alcohol (600 mL) was added to residue and then adjusted pH to 1-2 by aqueous hydrochloride. The mixture was cooled to about 10°-15°C, obtained solid was filtered and dried to get title compound. Wt- 95 gm. (HPLC Purity: 99.50 %)

Example-2
Method-a: Preparation of 3-dimethylaminomethyl-5-methyIhexan-2-one methiodide
Dimethyl amine hydrochloride (100 gm), paraformaldehyde (58.8 gm) and 5-methyl- 2-hexanone (560 gm) were added in methanol (300mL), temperature raised to reflux and stirred for about 8-10 hours. After completion of reaction, methanol and excess of 5-methyi-2-hexanone were completely distilled under vacuum. Water (400mL) was added and traces of 5-methyl-2-hexanone were removed by washing with dichloromethane (500mL). The aqueous layer pH was adjusted to 8-9 with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate (1000mL). Ethyl acetate layer was washed with 20% brine solution (300 mL), and then reacted with methyl iodide (206 gm) at about 15°-20 °C, stirred for about 8 hours at about 25°-30°C and filtered. The wet cake was taken in 5% aqueous isopropyl alcohol (700 mL), temperature raised to about 60°-65°C to get clear solution and stirred for 30 minutes. The reaction mass was cooled to about 25°-30°C, stirred for about 4 hours, filtered and dried to obtain title compound. Wt-170 gm. (HPLC Purity: 92.0 %; Isomer imp: 3.0 %)

Method-b: Preparation of 3-dimethylaminomethyl-5-methylhexan-2-one methiodide
Dimethyl amine hydrochloride (100 gm), paraformaldehyde (58.8 gm) and 5-Methyl- 2-hexanone (560gm) were added in methanol (300mL), temperature raised to reflux and stirred for about 8-10 hours. After completion of reaction, methanol and excess of 5-methyl-2-hexanone were completely distilled under vacuum. Purified water (400mL) was added and traces of 5-methyl-2-hexanone were removed by washing with dichloromethane (500mL). The aqueous layer pH was adjusted to 8-9 with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate (1000mL). Ethyl acetate layer was carried out by fractional distillation to collect the main fraction of the product and then reacted with methyl iodide (220 gm) at about 15°-20 °C, stirred for about 8 hrs at 25°-30°C. The obtained solid was filtered and dried to get title compound. Wt-220 gm. (HPLC Purity: 85.0 % Isomer imp: 10.0%)

Example-3
Method-a: Preparation of tetrabenazine.

6, 7-dimethoxy -3, 4-dihydro isoquinoline hydrochloride trihydrate (100 gm) was added in purified water (200mL) and pH 8-9 was adjusted using 20% potassium carbonate solution. Dichloromethane (500mL) was added to the reaction mass to separate the layers, to the dichloromethane layer purified water (400mL), 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (111.2gm) and of triethyl benzyl ammonium chloride (24gm) were added. Dichloromethane was distilled out and the reaction mass was stirred at about 93°-97°C for about 5 hrs. Ethyl acetate (800ml) was added at about 25°-35°C to resultant mass and separated the layers. The ethylacetate layer was distilled out completely under vacuum at below about 60°C to get a residue. To this residue isopropyl alcohol was added, heated to about 75°-80cC, then cooled to about 25°-30°C and stirred for about 2 hours at same temperature. Resultant solid was filtered and washed with isopropyl alcohol (50 mL). The wet cake was taken in isopropyl alcohol (600ml_), temperature raised to about 70°-80°C, stirred for about 10-20 minutes and then cooled to about 25°-30°C. The obtained solid was filtered, washed with I PA (50mL) and dried to get a tetrabenazine. Wt - 60 gm (HPLC Purity: 99.70%)

Method-b: Preparation of tetrabenazine.

6, 7-dimethoxy -3, 4-dihydro isoquinoline hydrochloride trihydrate (100gm) was added in purified water (200mL) and pH 8-9 was adjusted using 20% potassium carbonate solution. Dichloromethane (500ml_) was added to the reaction mass to separate the layers; to the dichloromethane layer purified water (400mL), 3-dimethylaminomethyl-5-methylhexan-2-one methiodide (111.2gm) and of triethyl benzyl ammonium chloride (24gm) were added. Dichloromethane was distilled out and the reaction mass was stirred at a temperature of 93°-97°C for 5 hours. Ethyl acetate (800mL) was added at about 25°-35°C to resultant mass and separated the layers. The ethylacetate layer was distilled out completely under vacuum at below about 60°C to get a residue. To this residue, acetone (300ml_) was added and pH 1-2 adjusted using aqueous hydrochloride; suspension was maintain at about 10°-15°C for about 1 hr and then filter, wash with chilled acetone (50mL). The resultant salt was taken into water (200mL) and adjusted pH 8-9 using aqueous ammonia. The aqueous layer was extracted with dichloromethane (300ml_), distilled off dichloromethane completely under vacuum. To the resultant mass, isopropyl alcohol (200mL) was added and stirred at about 25°-30°C for 1 hour; the obtain solid was filtered and dried to get tetrabenazine. Wt- 45 gm (HPLC Purity: 99.20%)

Example-4
Method-a: Purification of tetrabenazine
Tetrabenazine (100gm) was taken in isopropyl alcohol (lOOOmL) and heated to about 75°-80°C for 10-20 minutes. The resultant mass was filtered through micron filter and wash with hot isopropyl alcohol (100mL). Filtrate was allowed to cool at about 10°-15°C and stirred for about 2 hours. The solid obtained was filtered, washed with chilled isopropyl alcohol (50mL) and dried to get a pure Tetrabenazine. Wt - 92 gm (HPLC purity: 99.95 %)

Method-b: Purification of tetrabenazine

Tetrabenazine (100gm) was taken in ethanol (500mL) and heated to about 75°-80°C for 10-20 minutes. The resultant mass was filtered through micron filter and washed with hot ethanol (100mL). Filtrate was allowed to cool at about 10°-15°C and stirred for 2 hours. The solid obtained was filtered, washed with chilled ethanol (50mL) and dried to get a pure Tetrabenazine. Wt - 88 gm (HPLC purity: 99.95 %)

Method-c: Purification of tetrabenazine
Tetrabenazine (100gm) was taken in methanol (500mL) and heated to about 75°-80°C for 10-20
minutes. The resultant mass was filtered through micron filter and wash with hot methanol
(100ml_). Filtrate was allowed to cool at about 10°-15°C and stirred for 2 hours. The solid
obtained was filtered, washed with chilled methanol (50mL) and dried to get a pure
Tetrabenazine.

Wt-88 gm (HPLC purity: 99.95 %)

We claim:

1. A process for purification of 3-dimethylaminomethyl-5-methylhexan-2-one methiodide, the
process comprising the steps of;

a) suspending 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in a mixture of water and water miscible solvent,

b) heating the mixture to get a clear solution,

c) cooling the clear solution to room temperature, and

d) isolating pure 3-dimethylaminomethyl-5-methylhexan-2-one methiodide from the solution.

2. The process according to claim 1, wherein water miscible solvent is selected from the group consisting of methanol, ethanol and isopropanol.

3. A process for the preparation of substantially pure tetrabenazine, the process comprising the steps of;

a) reacting homoveratrylamine with ethylformate to form N-(3,4-dimethoxy phenethyl) acetamide,

b) reacting N-(3,4-dimethoxy phenethyl) acetamide obtained in step a) with phosphorus oxychloride to form 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride trihydrate,

c) reacting 6,7-dimethoxy-3,4-dihydroisoqui noline-hydrochloride trihydrate obtained in step b with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide as prepared according to claim 1, in the presence of a phase transfer catalyst to yield tetrabenazine,

d) optionally purifying the tetrabenazine obtained in step c), and
e) isolating pure tetrabenazine

4. The process according to claim 3, wherein the phase transfers catalyst is triethyl benzyl
ammonium chloride, tetrabutylammonium bromide (TBAB); tetrabutylammonium acetate;
tetrabutylammonium hydrogensulphate; tetraethylammonium bromide;
methyltributylammonium chloride (MTBAC); tetrabutylammonium hydroxide (TBAH);
benzyltrimethylammonium hydroxide (BTMAH); tetramethylammonium hydroxide (TMAH)
and tributylbenzylammonium chloride.

5. The process according to claim 3, wherein the reaction in step b) is carried out in acetonitrile solvent.

6. The process according to claim 3, wherein the reaction in step c) is carried out in water.

7. The process according to claim 3, wherein the tetrabenazine is purified using methanol, ethanol, or isopropanol solvent, or a mixture thereof.

8. Tetrabenazine having substantially free of one or more impurities of formulae (X), (XI), (XII), (XIII) and (XIV).