Claims:1. An improved process for preparing 3-dimethylaminomethyl-5-methyl-hexan-2-one of Formula (II),

the said process comprising the steps of
a) providing the mixture comprising an aqueous solution of dimethyl amine, aqueous solution of formaldehyde and suitable solvent;
b) adding conc. HCl and 5-methyl-2-hexanone of Formula (III)

to the reaction mixture obtained in step a);
c) heating the mixture at reflux temperature of solvent;
d) cooling the reaction mixture to 25-35°C;
e) adjusting the pH to about 10; and
f) isolating 3-dimethylaminomethyl-5-methyl-hexan-2-one from the crude reaction product mixture.
wherein 3-dimethylaminomethyl-5-methyl-hexan-2-one has GC purity greater than or equal to 95%.

2. The process according to claim 1, wherein the suitable solvent is selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol, dichloromethane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, acetamide, dimethyl formamide, ethyl acetate, propyl acetate, butyl acetate, toluene, n-hexane, benzene, heptane and water or any mixtures thereof.

3. The process according to claim 2, wherein the solvent is isopropyl alcohol.

4. The process according to claim 1, wherein the process for purification of 3-dimethylaminomethyl-5-methyl-hexan-2-one comprising the step of, subjecting the crude mixture to fractional distillation to provide 3-dimethylaminomethyl-5-methyl-hexan-2-one, which has GC purity greater than or equal to 95%.

5. An improved process for preparing tetrabenazine, the said process comprising the steps of:
a) reacting 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained according to claim 1 with 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride of Formula (IV)

Formula (IV)
in presence of suitable solvent; and
b) crystallizing crude tetrabenazine in presence of solvent.

6. The process according to claim 5, wherein the suitable solvent is selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol, dichloromethane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, acetamide, dimethyl formamide, ethyl acetate, propyl acetate, butyl acetate, toluene, n-hexane, benzene, heptane and water or any mixtures thereof.

7. The process according to claim 6, wherein the solvent is mixture of isopropyl alcohol and water.

8. The process for purification of 3-dimethylaminomethyl-5-methyl-hexan-2-one of Formula (II) or tetrabenazine comprising fractional distillation.

9. The process according to claim 5, wherein the crystallization solvent is a mixture of ethyl acetate and hexane.
, Description:Field of Invention

The present invention relates to an improved process for preparing 3-dimethylaminomethyl-5-methyl-hexan-2-one, which is one of the key starting material in the preparation of tetrabenazine. The present invention also provides an improved process for preparation of tetrabenazine. The product 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained according to present invention has Gas chromatography (GC) purity of greater than or equal to 95%.

Background of the invention

Tetrabenazine is a monoamine depletor for the treatment of chorea associated with Huntington's disease. Tetrabenazine is chemically described as 3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one of Formula (I).

Formula (I)

Tetrabenazine has been used as a drug for decades. Pletscher in science, 1957 described tetrabenazine is a compound commercially available as a racemic mixture and known for its antipsychotic and sedative properties.

U.S. Patent No. 7,897,768 discloses preparation of tetrabenazine by oxidation of allylic alcohol compound of Formula (VII)

followed by amino cyclization to provide tetrabenazine.

U.S. Patent No. 8,993,766 discloses method for preparing tetrabenazine by short reaction processes of using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 4-methyl-2-(3-(trimethylsilyl)prop-1-ene-2-yl)pentane as starting materials to sequentially perform an alkylation reaction, an Aza-Prins cyclization reaction in the presence of an oxidant and an oxidation reaction.

U.S. Patent No. 8,039,627 discloses preparation of tetrabenazine by reacting 6, 7-dimethoxy-3, 4-dihydroisoquinoline and 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide.

U.S. Patent No. 8,039,627 also discloses the preparation of 3-dimethylaminomethyl-5-methyl-hexan-2-one by mannich reaction of dimethylamine hydrochloride, 5-methyl-2-hexanone and paraformaldehyde in presence of conc. HCl and purified by flash column chromatography.

International PCT Publication No. WO 2012/081031 A2 discloses mannich reaction of dimethylamine hydrochloride, 5-methyl-2-hexanone and paraformaldehyde in presence of conc. HCl and extracted with toluene to provide 3-dimethylaminomethyl-5-methyl-hexan-2-one of HPLC purity 99.80%.

However by repeating the process disclosed in Example of WO 2012/081031 A2 in the lab scale, it provides 3-dimethylaminomethyl-5-methyl-hexan-2-one with multiple impurities, with compound purity of about 60-65% by GC.

Further in the reported processes, 3-dimethylaminomethyl-5-methyl-hexan-2-one is used as quaternary salt i.e. 3-dimethylaminomethyl-5-methyl-hexan-2-one methyl iodide which is further reacted with 6,7-dimethoxy-3,4-dihydroisoquinoline to obtain tetrabenazine.

The objective of the present invention is to provide purification process for the preparation of 3-dimethylaminomethyl-5-methyl-hexan-2-one of GC purity greater than or equal to 95% and improved process for preparation of tetrabenazine.

Summary of the Invention

In one aspect, the present invention relates to an improved process for preparing 3-dimethylaminomethyl-5-methyl-hexan-2-one of Formula (II) or salt thereof

the said process including the steps of
a) providing a mixture comprising an aqueous solution of dimethyl amine, aqueous solution of formaldehyde and suitable solvent;
b) adding hydrochloride and 5-methyl-2-hexanone of Formula (III) or salt thereof

to the reaction mixture obtained in step a);
c) heating the mixture at reflux temperature of solvent;
d) cooling the reaction mixture to 25-35°C;
e) adjusting the pH to about 10; and
f) isolating 3-dimethylaminomethyl-5-methyl-hexan-2-one from the crude reaction product mixture.
wherein 3-dimethylaminomethyl-5-methyl-hexan-2-one has GC purity greater than or equal to 95%.

In another aspect, the present invention relates to process for purification of 3-dimethylaminomethyl-5-methyl-hexan-2-one, comprising the step of, subjecting the crude reaction product mixture comprising 3-dimethylaminomethyl-5-methyl-hexan-2-one to fractional distillation to provide 3-dimethylaminomethyl-5-methyl-hexan-2-one of GC purity greater than or equal to 95%.

In another aspect, the present invention relates to an improved process for preparing tetrabenazine, the said process including the steps of
a) reacting 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained according to the present invention with 6, 7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride of Formula (IV)

Formula (IV)
in presence of suitable solvent; and
b) crystallizing crude tetrabenazine in presence of suitable solvent.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms such as "about", "general", "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at the very least, a degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, the term "Suitable solvent" means a single or a combination of two or more solvents.

As used herein, the term “reflux” refers to an experimental method that involves heating a reaction mixture to the boiling point temperature of the reaction solvent and inducing the solvent to recondense back into the reaction flask using a condenser.

3-dimethylaminomethyl-5-methyl-hexan-2-one of the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

In one aspect, the present invention relates to an improved process for preparing 3-dimethylaminomethyl-5-methyl-hexan-2-one of Formula (II) or salt thereof

the said process including the steps of
a) providing the mixture comprising an aqueous solution of dimethyl amine, aqueous solution of formaldehyde and suitable solvent;
b) adding hydrochloride and 5-methyl-2-hexanone of Formula (III)

to the reaction mixture obtained in step a);
c) heating the mixture at reflux temperature of solvent;
d) cooling the reaction mixture to 25-35°C;
e) adjusting the pH to about 10; and
f) isolating 3-dimethylaminomethyl-5-methyl-hexan-2-one from the crude reaction product mixture,
wherein 3-dimethylaminomethyl-5-methyl-hexan-2-one has GC purity greater than or equal to 95%.

In another aspect, the dimethyl amine and formaldehyde in step (a) is used in form of aqueous solution. The aqueous solvent is preferably water or a mixture of water and a C1 to a C4 alcohol. An exact amount for each component of the mixture is not required in the present invention. Rather, the mixture should have enough water to be aqueous in character. In one embodiment, the ratio of the water/solvent mixture is about 1:1 to 1:2 (vol/vol). In another embodiment, it is about 3:1 to 4:1 water/solvent. Higher water to solvent ratios are generally preferred. The alcohol is preferably a C1 to a C4 alcohol and most preferably methanol. In another embodiment, the concentration of dimethyl amine in aqueous solution is e.g. at least 40% by weight, preferably in the order of 40% to 50% by weight. In another embodiment, the concentration of formaldehyde in aqueous solution is e.g. at least 37% by weight, preferably in the order of 37% to 41% by weight.

In general, suitable solvent as in step (a) is selected from the group comprising one or more of alcohol, halogenated solvent, acetates, ether, hydrocarbon, water or mixture thereof. The alcohol selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol and the like; the halogenated solvent selected from the group comprising one or more of dichloromethane; the ether selected from the group comprising one or more of methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; the amides selected from the group comprising one or more of dimethyl acetamide and dimethyl formamide and the like; the acetate selected from the group comprising one or more of ethyl acetate, propyl acetate, butyl acetate and the like; hydrocarbon selected from the group comprising one or more of toluene, n-hexane, benzene, heptane and the like.

More preferably, the solvent in step (a) is isopropyl alcohol.

In general, the reaction mixture of step (b) is heating at a reflux temperature of solvent.

More preferably the reaction mixture of step (b) is heating to temperature in between range of 80°-85° C.

In another aspect, the present invention relates to process for purification of 3-dimethylaminomethyl-5-methyl-hexan-2-one comprising the step of, subjecting the crude mixture to fractional distillation to provide 3-dimethylaminomethyl-5-methyl-hexan-2-one, which has GC purity greater than or equal to 95%.

As used herein, the term “crude mixture” means the crude 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained after the initial reaction mixture has been reacted.

The fractional distillation method per se is well known to the man skilled in the art and, in general terms, it consists in the vaporization of a liquid phase by heating and in the subsequent condensation by cooling in a site differing from that used for vaporization; in the specific case of fractional distillation between said vaporization site and that for condensation, a fractionating column is inserted to increase the efficiency of the separation process.

Moreover, it is important to note that in a fractional distillation process the control of the operating parameters can be ensured on industrial scale with simpler methods and thus at a lower cost than in a chromatographic process. A confirmation of this is the large diffusion of fractional distillation in the oil and petrochemical industry wherein the process is typically carried out in continuous.

In general, a fractionating column with more than 6 theoretical plates is preferably used, the distillation being carried out continuously.

According to present invention, the fraction separated at a vapor temperature in between range of 42°C to 50°C at a vacuum of 5 mm or less was collected and analyzed by GC. This fraction may be subjected to one or more cycles to obtain 3-dimethylaminomethyl-5-methyl-hexan-2-one of GC purity greater than or equal to 95%.

In another aspect, the present invention relates to purification of 3-dimethylaminomethyl-5-methyl-hexan-2-one of Formula (II) or tetrabenazine of Formula (I) by fractional distillation or steam distillation.

In another aspect, the present invention relates to an improved process for preparing tetrabenazine, the said process including the steps of
a. reacting 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained according to the present invention with 6, 7-dimethoxy-3,4-dihydroisoquinoline hydrochloride of Formula (IV)

Formula (IV)
in presence of suitable solvent; and
b. crystallizing crude tetrabenazine in presence of solvent.

In general, suitable solvent as in step (a) is selected from the group comprising one or more of alcohol, halogenated solvent, acetates, ether, hydrocarbon, water or mixture thereof. The alcohol selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol and the like; the halogenated solvent selected from the group comprising one or more of dichloromethane; the ether selected from the group comprising one or more of methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; the amides selected from the group comprising one or more of dimethyl acetamide and dimethyl formamide and the like; the acetate selected from the group comprising one or more of ethyl acetate, propyl acetate, butyl acetate and the like; hydrocarbon selected from the group comprising one or more of toluene, n-hexane, benzene, heptane and the like.

More preferably, the solvent in step (a) is mixture of isopropyl alcohol and water.

In another aspect, the crude tetrabenazine is subject to crystallization by providing tetrabenazine in one or more solvents by heating at temperature in between range of 80°C -85°C and obtaining the substantially pure tetrabenazine by removal of solvent.

In general the removal of the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

According to the present solvent, the crystallization solvent for tetrabenazine in step (b) comprises one or more of alcohol, halogenated solvent, acetates, ether, hydrocarbon, water or mixture thereof. The alcohol such as methanol, ethanol, isopropyl alcohol and the like; the halogenated solvent such as dichloromethane; the ether such as methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; the amides such as dimethyl acetamide and dimethyl formamide and the like; the acetate such as ethyl acetate, propyl acetate, butyl acetate and the like; hydrocarbon such as toluene, n-hexane, benzene, heptane and the like.

More preferably, the solvent for crystallization of tetrabenazine is mixture of ethyl acetate and hexane.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example1: Preparation of 3-dimethylaminomethyl-5-methyl-hexan-2-one

Aqueous dimethyl amine solution (0.89 L, 40% W/V) and isopropyl alcohol (3.5 L) were combined to form a mixture. The mixture was cooled to temperature about 0°C to 5°C. To the mixture, aqueous formaldehyde solution (0.64 L, 37% W/V) and concentrated hydrochloric acid were added at temperature 5°C and heated to temperature about 80°C to 85°C. After completion of the reaction, the reaction mixture was cooled to at temperature 40° C and distilled under reduced pressure till the residual volume of solvent obtained. The concentrated solution was cooled to temperature 25°-35°C and pH of 9.5 to 10.5 was adjusted with 20% W/V sodium hydroxide solution and extracted one or more times with ethyl acetate. The organic layers were combined and concentrated under vacuum till the residual volume of solvent obtained. The concentrated solution was subjected to fractional distillation. The fraction obtained was collected separately at vapor temperature of 35°C to 55°C. This fraction is subjected to one more cycle of fractional distillation under vacuum to get title compound of purity of about 95% (relative, by G.C.).
Yield: 0.4 kg/kg
GC Purity: 95.5 %

Example 2: Preparation of Tetrabenazine

1 mol of 3-dimethylaminomethyl-5-methyl-hexan-2-one obtained in Example 1 was reacted with 1 mol of 6, 7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride in a mixture of isopropyl alcohol (5V) and water (5V). The reaction mixture was heated to 80°C to 85°C for 36 hours. After completion of the reaction, the reaction mass was cooled to room temperature and seeded with tetrabenazine. The reaction mass was further cooled to temperature 0°C to 5°C and stirred for the period of 1 hour. The resulting slurry was then filtered under vacuum and the wet cake is washed with isopropyl alcohol (2V). The obtained solid was dried under vacuum to get crude Tetrabenazine, which was further recrystallized from mixture of ethyl acetate and hexane to give crystalline title compound of HPLC purity 99%.